Hepatitis C virus inhibitors

ABSTRACT

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. non-provisionalapplication Ser. No. 11/835,462, filed Aug. 8, 2007, and claims thebenefit of U.S. provisional application No. 60/836,996, filed Aug. 11,2006.

The present disclosure is generally directed to antiviral compounds, andmore specifically directed to compounds which can inhibit the functionof the NS5A protein encoded by Hepatitis C virus (HCV), compositionscomprising such compounds, and methods for inhibiting the function ofthe NS5A protein.

HCV is a major human pathogen, infecting an estimated 170 millionpersons worldwide—roughly five times the number infected by humanimmunodeficiency virus type 1. A substantial fraction of these HCVinfected individuals develop serious progressive liver disease,including cirrhosis and hepatocellular carcinoma.

Presently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients. Recent clinical results demonstrate that pegylatedalpha-interferon is superior to unmodified alpha-interferon asmonotherapy. However, even with experimental therapeutic regimensinvolving combinations of pegylated alpha-interferon and ribavirin, asubstantial fraction of patients do not have a sustained reduction inviral load. Thus, there is a clear and long-felt need to developeffective therapeutics for treatment of HCV infection.

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the 5′untranslated region, HCV has been classified as a separate genus in theFlaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome. At least six majorgenotypes have been characterized, and more than 50 subtypes have beendescribed. The major genotypes of HCV differ in their distributionworldwide, and the clinical significance of the genetic heterogeneity ofHCV remains elusive despite numerous studies of the possible effect ofgenotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to herein as NS3 protease) andmediates all the subsequent cleavages downstream of NS3, both in cis, atthe NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions, acting as a cofactor for the NS3 protease and possiblyassisting in the membrane localization of NS3 and other viral replicasecomponents. The complex formation of the NS3 protein with NS4A seemsnecessary to the processing events, enhancing the proteolytic efficiencyat all of the sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. NS5B (also referred toherein as HCV polymerase) is a RNA-dependent RNA polymerase that isinvolved in the replication of HCV.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in Tan, S.-L.,Katzel, M. G. Virology 2001, 284, 1-12; and in Park, K.-J.; Choi, S.-H,J. Biological Chemistry 2003.

In a first aspect the present disclosure provides a compound of Formula(I)

or a pharmaceutically acceptable salt thereof, wherein

m and n are independently 0, 1, or 2;

q and s are independently 0, 1, 2, 3, or 4;

u and v are independently 0, 1, 2, or 3;

X is selected from O, S, S(O), SO₂, CH₂, CHR⁵, and C(R⁵)₂;

provided that when n is 0, X is selected from CH₂, CHR⁵, and C(R⁵)₂;

Y is selected from O, S, S(O), SO₂, CH₂, CHR⁶, and C(R⁶)₂;

provided that when m is 0, Y is selected from CH₂, CHR⁶, and C(R⁶)₂;

each R¹ and R² is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (R^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl;

R³ and R⁴ are each independently selected from hydrogen, R⁹—C(O)—, andR⁹—C(S)—;

each R⁵ and R⁶ is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(a)R^(b), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

R⁷ and R⁸ are each independently selected from hydrogen, alkoxycarbonyl,alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NR^(a)R^(b))carbonyl,and trialkylsilylalkoxyalkyl; and

each R⁹ is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),R^(c)R^(d))alkenyl, (R^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl.

In a first embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein m and n are each 1.

In a second embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein

u and v are each independently 0, 1, or 2; and

each R¹ and R² is independently selected from alkoxy, alkoxyalkyl,alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl,hydroxyalkyl, (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl.

In a third embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein

u and v are each independently 0 or 1; and

when present, R¹ and/or R² are halo.

In a fourth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein

u and v are each independently 0 or 1; and

when present, R¹ and/or R² are halo, wherein the halo is fluoro.

In a fifth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein at least one of X and Y is S.

In a sixth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein X and Y are each S.

In a seventh embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein X is selected from CHR⁵, and C(R⁵)₂; and Y isselected from CH₂, CHR⁶, and C(R⁶)₂.

In an eighth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein R⁷ and R⁸ are independently selected fromhydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl,and (NR^(a)R^(b))carbonyl.

In a ninth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein R⁷ and R⁸ are each hydrogen.

In a tenth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein

q and s are independently 0, 1, or 2; and

each R⁵ and R⁶ is independently selected from alkyl, aryl, halo, andhydroxy, wherein the alkyl can optionally form a fused three- tosix-membered ring with an adjacent carbon atom, wherein the three- tosix-membered ring is optionally substituted with one or two alkylgroups.

In an eleventh embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein

q and s are independently 0 or 1; and

when present, R⁵ and/or R⁶ are each halo.

In a twelfth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein

q and s are independently 0 or 1; and

when present, R⁵ and/or R⁶ are each halo, wherein the halo is fluoro.

In a thirteenth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein at least one of R³ and R⁴ is hydrogen.

In a fourteenth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein R³ and R⁴ are each R⁹—C(O)—.

In a fifteenth embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein each R⁹ is independently selected from alkoxy,alkoxyalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy,arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl,—NR^(c)R^(d), (NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and(NR^(c)R^(d))carbonyl.

In a second aspect the present disclosure provides a compound of Formula(II)

or a pharmaceutically acceptable salt thereof, wherein

q and s are independently 0, 1, or 2;

u and v are independently 0, 1, or 2;

X is selected from S, CH₂, CHR⁵, and C(R⁵)₂;

Y is selected from S, CH₂, CHR⁶, and C(R⁶)₂;

each R¹ and R² is independently selected from alkoxy, alkoxyalkyl,alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl,hydroxyalkyl, (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;

R³ and R⁴ are each independently selected from hydrogen and R⁹—C(O)—;

each R⁵ and R⁶ is independently selected from alkyl, aryl, halo, andhydroxy, wherein the alkyl can optionally form a fused three- tosix-membered ring with an adjacent carbon atom, wherein the three- tosix-membered ring is optionally substituted with one or two alkylgroups;

R⁷ and R⁸ are each independently selected from hydrogen, alkoxycarbonyl,alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, and(NR^(a)R^(b))carbonyl; and

each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkyl,alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl,aryloxyalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl,heterocyclyl, heterocyclylalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl.

In a third aspect the present disclosure provides a compound of Formula(III)

or a pharmaceutically acceptable salt thereof, wherein

q and s are independently 0, 1, or 2;

u and v are independently 0 or 1;

X is selected from CH₂, CHR⁵, and C(R⁵)₂;

Y is selected from CH₂, CHR⁶, and C(R⁶)₂;

when present, R¹ and/or R² are halo, wherein the halo is fluoro;

R³ and R⁴ are each R⁹—C(O)—;

when present, R⁵ and/or R⁶ are halo, wherein the halo is fluoro; and

each R⁹ is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl.

In a fourth aspect the present disclosure provides a compound selectedfrom

-   methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;-   (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine);-   methyl((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;-   methyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;-   methyl((1S)-1-(((1R,3R,5R)-3-(5-(4′-(2-((1R,3R,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;-   methyl((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate;-   methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;-   methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;-   dimethyl    (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate;-   (1R)—N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine;-   methyl((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;    and-   methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2,2-dimethylpropyl)carbamate;    or a pharmaceutically acceptable salt thereof.

In a first embodiment of the fifth aspect the pharmaceuticallyacceptable salt is a dihydrochloride salt.

In a sixth aspect the present disclosure provides a compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

In a first embodiment of the sixth aspect the composition furthercomprises one or two additional compounds having anti-HCV activity. In asecond embodiment at least one of the additional compounds is aninterferon or a ribavirin. In a third embodiment the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastoid interferon tau.

In a fourth embodiment of the sixth aspect the composition furthercomprises one or two additional compounds having anti-HCV activitywherein at least one of the additional compounds is selected frominterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

In a fifth embodiment of the sixth aspect the composition furthercomprises one or two additional compounds having anti-HCV activitywherein at least one of the additional compounds is effective to inhibitthe function of a target selected from HCV metalloprotease, HCV serineprotease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCVassembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment ofan HCV infection.

In an seventh aspect the present disclosure provides a method oftreating an HCV infection in a patient, comprising administering to thepatient a therapeutically effective amount of a compound of formula (J),or a pharmaceutically acceptable salt thereof.

In a first embodiment of the seventh aspect the method further comprisesadministering one or two additional compounds having anti-HCV activityprior to, after or simultaneously with the compound of formula (I), or apharmaceutically acceptable salt thereof. In a second embodiment atleast one of the additional compounds is an interferon or a ribavirin.In a third embodiment the interferon is selected from interferon alpha2B, pegylated interferon alpha, consensus interferon, interferon alpha2A, and lymphoblastoid interferon tau.

In a fourth embodiment the method further comprises administering one ortwo additional compounds having anti-HCV activity prior to, after orsimultaneously with the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, wherein at least one of the additionalcompounds is selected from interleukin 2, interleukin 6, interleukin 12,a compound that enhances the development of a type 1 helper T cellresponse, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, aninosine 5′-monophospate dehydrogenase inhibitor, amantadine, andrimantadine.

In a fifth embodiment the method further comprises administering one ortwo additional compounds having anti-HCV activity prior to, after orsimultaneously with the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, wherein at least one of the additionalcompounds is effective to inhibit the function of a target selected fromHCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase,HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein,and IMPDH for the treatment of an HCV infection.

Other embodiments of the present disclosure may comprise suitablecombinations of two or more of embodiments and/or aspects disclosedherein.

Yet other embodiments and aspects of the disclosure will be apparentaccording to the description provided below.

The compounds of the present disclosure also exist as tautomers;therefore the present disclosure also encompasses all tautomeric forms.

The description of the present disclosure herein should be construed incongruity with the laws and principals of chemical bonding. In someinstances it may be necessary to remove a hydrogen atom in orderaccommodate a substitutent at any given location. For example, in thestructure shown below

R⁸ may be attached to either the carbon atom in the imidazole ring or,alternatively, R⁸ may take the place of the hydrogen atom on thenitrogen ring to form an N-substituted imidazole.

It should be understood that the compounds encompassed by the presentdisclosure are those that are suitably stable for use as pharmaceuticalagent.

It is intended that the definition of any substituent or variable (e.g.,R¹, R², R⁵, R⁶, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. For example,when u is 2, each of the two R¹ groups may be the same or different.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

As used in the present specification, the following terms have themeanings indicated:

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groupsof the present disclosure may be substituted as described in each oftheir respective definitions. For example, the aryl part of an arylalkylgroup may be substituted as described in the definition of the term‘aryl’.

The term “alkenyl,” as used herein, refers to a straight or branchedchain group of two to six carbon atoms containing at least onecarbon-carbon double bond.

The term “alkenyloxy,” as used herein, refers to an alkenyl groupattached to the parent molecular moiety through an oxygen atom.

The term “alkenyloxycarbonyl,” as used herein, refers to an alkenyloxygroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkoxy groups.

The term “alkoxyalkylcarbonyl,” as used herein, refers to an alkoxyalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkoxycarbonyl groups.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing from one tosix carbon atoms. In the compounds of the present disclosure, when mand/or n is 1 or 2; X and/or Y is CHR⁵ and/or CHR⁶, respectively, and R⁵and/or R⁶ is alkyl, each alkyl can optionally form a fused three- tosix-membered ring with an adjacent carbon atom to provide one of thestructures shown below:

where z is 1, 2, 3, or 4, w is 0, 1, or 2, and R⁵⁰ is alkyl. When w is2, the two R⁵⁰ alkyl groups may be the same or different.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylcarbonylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkylcarbonyl groups.

The term “alkylcarbonyloxy,” as used herein, refers to an alkylcarbonylgroup attached to the parent molecular moiety through an oxygen atom.

The term “alkylsulfanyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfur atom.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicfused ring system wherein one or both of the rings is a phenyl group.Bicyclic fused ring systems consist of a phenyl group fused to a four-to six-membered aromatic or non-aromatic carbocyclic ring. The arylgroups of the present disclosure can be attached to the parent molecularmoiety through any substitutable carbon atom in the group.Representative examples of aryl groups include, but are not limited to,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The arylgroups of the present disclosure are optionally substituted with one,two, three, four, or five substituents independently selected fromalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second arylgroup, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy,haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,hydroxy, hydroxyalkyl, nitro, —NR^(x)R^(y), (NR^(x)R^(y)) alkyl, oxo,and —P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro.

The term “arylalkenyl,” as used herein, refers to an alkenyl groupsubstituted with one, two, or three aryl groups.

The term “arylalkoxy,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “arylalkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three arylalkoxy groups.

The term “arylalkoxyalkylcarbonyl,” as used herein, refers to anarylalkoxyalkyl group attached to the parent molecular moiety through acarbonyl group.

The term “arylalkoxycarbonyl,” as used herein, refers to an arylalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups. The alkyl part of thearylalkyl is further optionally substituted with one or two additionalgroups independently selected from alkoxy, alkylcarbonyloxy, halo,haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and —NR^(c)R^(d), whereinthe heterocyclyl is further optionally substituted with one or twosubstituents independently selected from alkoxy, alkyl, unsubstitutedaryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo,haloalkoxy, haloalkyl, hydroxy, and —NR^(x)R^(y).

The term “arylalkylcarbonyl,” as used herein, refers to an arylalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “aryloxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryloxy groups.

The term “aryloxycarbonyl,” as used herein, refers to an aryloxy groupattached to the parent molecular moiety through a carbonyl group.

The term “arylsulfonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a sulfonyl group.

The terms “Cap” and “cap” as used herein, refer to the group which isplaced on the nitrogen atom of the terminal nitrogen-containing ring,i.e., the pyrrolidine rings of compound 1e. It should be understood that“Cap” or “cap” can refer to the reagent used to append the group to theterminal nitrogen-containing ring or to the fragment in the finalproduct, i.e., “Cap-51” or “The Cap-51 fragment found in LS-19”.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,hydrocarbon ring system having three to seven carbon atoms and zeroheteroatoms. Representative examples of cycloalkyl groups include, butare not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. Thecycloalkyl groups of the present disclosure are optionally substitutedwith one, two, three, four, or five substituents independently selectedfrom alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy, hydroxyalkyl, nitro, and —NR^(x)R^(y), whereinthe aryl and the heterocyclyl are further optionally substituted withone, two, or three substituents independently selected from alkoxy,alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.

The term “(cycloalkyl)alkenyl,” as used herein, refers to an alkenylgroup substituted with one, two, or three cycloalkyl groups.

The term “(cycloalkyl)alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cycloalkyl groups. The alkyl part ofthe (cycloalkyl)alkyl is further optionally substituted with one or twogroups independently selected from hydroxy and —NR^(c)R^(d).

The term “cycloalkyloxy,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “cycloalkyloxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cycloalkyloxy groups.

The term “cycloalkylsulfonyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “formyl,” as used herein, refers to —CHO.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, orI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkoxycarbonyl,” as used herein, refers to a haloalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “heterocyclyl,” as used herein, refers to a four-, five-, six-,or seven-membered ring containing one, two, three, or four heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Thefour-membered ring has zero double bonds, the five-membered ring haszero to two double bonds, and the six- and seven-membered rings havezero to three double bonds. The term “heterocyclyl” also includesbicyclic groups in which the heterocyclyl ring is fused to anothermonocyclic heterocyclyl group, or a four- to six-membered aromatic ornon-aromatic carbocyclic ring; as well as bridged bicyclic groups suchas 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and2-azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the presentdisclosure can be attached to the parent molecular moiety through anycarbon atom or nitrogen atom in the group. Examples of heterocyclylgroups include, but are not limited to, benzothienyl, furyl, imidazolyl,indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl,piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl,pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, thiomorpholinyl,7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and2-azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the presentdisclosure are optionally substituted with one, two, three, four, orfive substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(x)R^(y), (NR^(x)R^(y))alkyl, and oxo, wherein the alkyl part of thearylalkyl and the heterocyclylalkyl are unsubstituted and wherein thearyl, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl,the second heterocyclyl group, and the heterocyclyl part of theheterocyclylalkyl and the heterocyclylcarbonyl are further optionallysubstituted with one, two, or three substituents independently selectedfrom alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “heterocyclylalkenyl,” as used herein, refers to an alkenylgroup substituted with one, two, or three heterocyclyl groups.

The term “heterocyclylalkoxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an alkoxy group.

The term “heterocyclylalkoxycarbonyl,” as used herein, refers to aheterocyclylalkoxy group attached to the parent molecular moiety througha carbonyl group.

The term “heterocyclylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three heterocyclyl groups. The alkyl partof the heterocyclylalkyl is further optionally substituted with one ortwo additional groups independently selected from alkoxy,alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(c)R^(d), wherein the aryl is further optionally substituted withone or two substituents independently selected from alkoxy, alkyl,unsubstituted aryl, unsubstituted arylalkoxy, unsubstitutedarylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(x)R^(y).

The term “heterocyclylalkylcarbonyl,” as used herein, refers to aheterocyclylalkyl group attached to the parent molecular moiety througha carbonyl group.

The term “heterocyclylcarbonyl,” as used herein, refers to aheterocyclyl group attached to the parent molecular moiety through acarbonyl group.

The term “heterocyclyloxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an oxygen atom.

The term “heterocyclyloxyalkyl,” as used herein, refers to an alkylgroup substituted with one, two, or three heterocyclyloxy groups.

The term “heterocyclyloxycarbonyl,” as used herein, refers to aheterocyclyloxy group attached to the parent molecular moiety through acarbonyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three hydroxy groups.

The term “hydroxyalkylcarbonyl,” as used herein, refers to ahydroxyalkyl group attached to the parent molecular moiety through acarbonyl group.

The term “nitro,” as used herein, refers to —NO₂.

The term “—NR^(a)R^(b),” as used herein, refers to two groups, R^(a) andR^(b), which are attached to the parent molecular moiety through anitrogen atom. R^(a) and R^(b) are independently selected from hydrogen,alkenyl, and alkyl.

The term “(NR^(a)R^(b))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(a)R^(b) groups.

The term “(NR^(a)R^(b))carbonyl,” as used herein, refers to an—NR^(a)R^(b) group attached to the parent molecular moiety through acarbonyl group.

The term “—NR^(c)R^(d),” as used herein, refers to two groups, R^(c) andR^(d), which are attached to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(x)R^(y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^(c)R^(d))alkenyl,” as used herein, refers to an alkenylgroup substituted with one, two, or three —NR^(c)R^(d) groups.

The term “(NR^(c)R^(d))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(c)R^(d) groups. The alkyl partof the (NR^(c)R^(d))alkyl is further optionally substituted with one ortwo additional groups selected from alkoxy, alkoxyalkylcarbonyl,alkoxycarbonyl, alkylsulfanyl, arylalkoxyalkylcarbonyl, carboxy,heterocyclyl, heterocyclylcarbonyl, hydroxy, and (NR^(e)R^(f))carbonyl;wherein the heterocyclyl is further optionally substituted with one,two, three, four, or five substituents independently selected fromalkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^(c)R^(d))carbonyl,” as used herein, refers to an—NR^(c)R^(d) group attached to the parent molecular moiety through acarbonyl group.

The term “—NR^(e)R^(f),” as used herein, refers to two groups, R^(e) andR^(f) which are attached to the parent molecular moiety through anitrogen atom. R^(e) and R^(f) are independently selected from hydrogen,alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstitutedcycloalkyl, unsubstituted (cycloalkyl)alkyl, unsubstituted heterocyclyl,unsubstituted heterocyclylalkyl, (NR^(x)R^(y))alkyl, and(NR^(x)R^(y))carbonyl.

The term “(NR^(e)R^(f))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(e)R^(f) groups.

The term “(NR^(e)R^(f))alkylcarbonyl,” as used herein, refers to an(NR^(e)R^(f))alkyl group attached to the parent molecular moiety througha carbonyl group.

The term “(NR^(e)R^(f))carbonyl,” as used herein, refers to an—NR^(e)R^(f) group attached to the parent molecular moiety through acarbonyl group.

The term “(NR^(e)R^(f))sulfonyl,” as used herein, refers to an—NR^(e)R^(f) group attached to the parent molecular moiety through asulfonyl group.

The term “—NR^(x)R^(y),” as used herein, refers to two groups, R^(x) andR^(y), which are attached to the parent molecular moiety through anitrogen atom. R^(x) and R^(y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(x)R^(y))carbonyl, wherein R^(x′)and R^(y′) are independently selected from hydrogen and alkyl.

The term “(NR^(x)R^(y))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(x)R^(y) groups.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂—.

The term “trialkylsilyl,” as used herein, refers to —SiR₃, wherein R isalkyl. The R groups may be the same or different.

The term “trialkylsilylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three trialkylsilyl groups.

The term “trialkylsilylalkoxy,” as used herein, refers to atrialkylsilylalkyl group attached to the parent molecular moiety throughan oxygen atom.

The term “trialkylsilylalkoxyalkyl,” as used herein, refers to an alkylgroup substituted with one, two, or three trialkylsilylalkoxy groups.

Asymmetric centers exist in the compounds of the present disclosure.These centers are designated by the symbols “R” or “S”, depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, or mixtures thereof, which possess the ability toinhibit NS5A. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of enantiomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

Certain compounds of the present disclosure may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present disclosure includes eachconformational isomer of these compounds and mixtures thereof.

The term “compounds of the present disclosure”, and equivalentexpressions, are meant to embrace compounds of Formula (I), andpharmaceutically acceptable enantiomers, diastereomers, and saltsthereof. Similarly, references to intermediates are meant to embracetheir salts where the context so permits.

The compounds of the present disclosure can exist as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent disclosure which are water or oil-soluble or dispersible, whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use The salts can be prepared during the final isolationand purification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate;digluconate, dihydrobromide, dihydrochloride, dihydroiodide,glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,lactate, maleate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,phosphate, glutamate, bicarbonate, para-toluenesulfonate, andundecanoate. Examples of acids which can be employed to formpharmaceutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,and N,N′-dibenzylethylenediamine. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as pharmaceuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcomposition. Accordingly, the disclosure further provides pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “therapeutically effective amount,” as used herein,refers to the total amount of each active component that is sufficientto show a meaningful patient benefit, e.g., a reduction in viral load.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially,or simultaneously. The compounds of formula (I) and pharmaceuticallyacceptable salts thereof, are as described above. The carrier(s),diluent(s), or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the present disclosure there is also provided a process for thepreparation of a pharmaceutical formulation including admixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,with one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “pharmaceutically acceptable,” as used herein,refers to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Dosage levels of between about 0.01 and about 250 milligram per kilogram(“mg/kg”) body weight per day, preferably between about 0.05 and about100 mg/kg body weight per day of the compounds of the present disclosureare typical in a monotherapy for the prevention and treatment of HCVmediated disease. Typically, the pharmaceutical compositions of thisdisclosure will be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage formwill vary depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight, and condition of the patient. Preferredunit dosage formulations are those containing a daily dose or sub-dose,as herein above recited, or an appropriate fraction thereof, of anactive ingredient. Treatment may be initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. In general, the compound is mostdesirably administered at a concentration level that will generallyafford antivirally effective results without causing any harmful ordeleterious side effects.

When the compositions of this disclosure comprise a combination of acompound of the present disclosure and one or more additionaltherapeutic or prophylactic agent, both the compound and the additionalagent are usually present at dosage levels of between about 10 to 150%,and more preferably between about 10 and 80% of the dosage normallyadministered in a monotherapy regimen.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intracutaneous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional, intravenous, or intradermalinjections or infusions) route. Such formulations may be prepared by anymethod known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) or excipient(s).Oral administration or administration by injection are preferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluent or base as described above, and optionally,with a binder such as carboxymethylcellulose, an aliginate, gelating, orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin, or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present disclosure can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of formula (I), and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research 1986,3(6), 318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and soutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The term “patient” includes both human and other mammals.

The term “treating” refers to: (i) preventing a disease, disorder orcondition from occurring in a patient that may be predisposed to thedisease, disorder, and/or condition but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, disorder, or condition, i.e.,arresting its development; and (iii) relieving the disease, disorder, orcondition, i.e., causing regression of the disease, disorder, and/orcondition.

The compounds of the present disclosure can also be administered with acyclosporin, for example, cyclosporin A. Cyclosporin A has been shown tobe active against HCV in clinical trials (Hepatology 2003, 38, 1282;Biochem. Biophys. Res. Commun. 2004, 313, 42; J. Gastroenterol. 2003,38, 567).

Table 1 below lists some illustrative examples of compounds that can beadministered with the compounds of this disclosure. The compounds of thedisclosure can be administered with other anti-HCV activity compounds incombination therapy, either jointly or separately, or by combining thecompounds into a composition.

TABLE 1 Physiological Type of Inhibitor or Source Brand Name ClassTarget Company NIM811 Cyclophilin Novartis Inhibitor ZadaxinImmunomodulator Sciclone Suvus Methylene blue Bioenvision Actilon(CPG10101) TLR9 agonist Coley Batabulin (T67) Anticancer β-tubulininhibitor Tularik Inc., South San Francisco, CA ISIS 14803 Antiviralantisense ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan PhamaceuticalsInc., New York, NY Summetrel Antiviral antiviral Endo PharmaceuticalsHoldings Inc., Chadds Ford, PA GS-9132 (ACH-806) Antiviral HCV InhibitorAchillion/ Gilead Pyrazolopyrimidine Antiviral HCV Inhibitors Arrowcompounds and salts Therapeutics From WO- Ltd. 2005047288 26 May 2005Levovirin Antiviral IMPDH inhibitor Ribapharm Inc., Costa Mesa, CAMerimepodib Antiviral IMPDH inhibitor Vertex (VX-497) PharmaceuticalsInc., Cambridge, MA XTL-6865 (XTL-002) Antiviral monoclonal XTL antibodyBiopharmaceuticals Ltd., Rehovot, Isreal Telaprevir Antiviral NS3 serineprotease Vertex (VX-950, LY-570310) inhibitor Pharmaceuticals Inc.,Cambridge, MA/Eli Lilly and Co. Inc., Indianapolis, IN HCV-796 AntiviralNS5B Replicase Wyeth/ Inhibitor Viropharma NM-283 Antiviral NS5BReplicase Idenix/ Inhibitor Novartis GL-59728 Antiviral NS5B ReplicaseGene Labs/ Inhibitor Novartis GL-60667 Antiviral NS5B Replicase GeneLabs/ Inhibitor Novartis 2′C MeA Antiviral NS5B Replicase GileadInhibitor PSI 6130 Antiviral NS5B Replicase Roche Inhibitor R1626Antiviral NS5B Replicase Roche Inhibitor 2′C Methyl adenosine AntiviralNS5B Replicase Merck Inhibitor JTK-003 Antiviral RdRp inhibitor JapanTobacco Inc., Tokyo, Japan Levovirin Antiviral ribavirin ICNPharmaceuticals, Costa Mesa, CA Ribavirin Antiviral ribavirin Schering-Plough Corporation, Kenilworth, NJ Viramidine Antiviral RibavirinProdrug Ribapharm Inc., Costa Mesa, CA Heptazyme Antiviral ribozymeRibozyme Pharmaceuticals Inc., Boulder, CO BILN-2061 Antiviral serineprotease Boehringer inhibitor Ingelheim Pharma KG, Ingelheim, GermanySCH 503034 Antiviral serine protease Schering inhibitor Plough ZadazimImmune Immune modulator SciClone modulator Pharmaceuticals Inc., SanMateo, CA Ceplene Immunomodulator immune modulator Maxim PharmaceuticalsInc., San Diego, CA CellCept Immunosuppressant HCV IgG F. Hoffmann-immunosuppressant La Roche LTD, Basel, Switzerland CivacirImmunosuppressant HCV IgG Nabi immunosuppressant BiopharmaceuticalsInc., Boca Raton, FL Albuferon-α Interferon albumin IFN-α2b Human GenomeSciences Inc., Rockville, MD Infergen A Interferon IFN alfacon-1InterMune Pharmaceuticals Inc., Brisbane, CA Omega IFN Interferon IFN-ωIntarcia Therapeutics IFN-β and EMZ701 Interferon IFN-β and EMZ701Transition Therapeutics Inc., Ontario, Canada Rebif Interferon IFN-β1aSerono, Geneva, Switzerland Roferon A Interferon IFN-α2a F. Hoffmann- LaRoche LTD, Basel, Switzerland Intron A Interferon IFN-α2b Schering-Plough Corporation, Kenilworth, NJ Intron A and Zadaxin InterferonIFN-α2b/α1- RegeneRx thymosin Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc, San Mateo, CA Rebetron InterferonIFN-α2b/ribavirin Schering- Plough Corporation, Kenilworth, NJ ActimmuneInterferon INF-γ InterMune Inc., Brisbane, CA Interferon-β InterferonInterferon-β-1a Serono Multiferon Interferon Long lasting IFNViragen/Valentis Wellferon Interferon lymphoblastoid GlaxoSmithKlineIFN-αn1 plc, Uxbridge, UK Omniferon Interferon natural IFN-α ViragenInc., Plantation, FL Pegasys Interferon PEGylated IFN-α2a F. Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and Ceplene InterferonPEGylated IFN- Maxim α2a/ Pharmaceuticals immune modulator Inc., SanDiego, CA Pegasys and Ribavirin Interferon PEGylated IFN- F. Hoffmann-α2a/ribavirin La Roche LTD, Basel, Switzerland PEG-Intron InterferonPEGylated IFN-α2b Schering- Plough Corporation, Kenilworth, NJPEG-Intron/ Interferon PEGylated IFN- Schering- Ribavirin α2b/ribavirinPlough Corporation, Kenilworth, NJ IP-501 Liver protection antifibroticIndevus Pharmaceuticals Inc., Lexington, MA IDN-6556 Liver protectioncaspase inhibitor Idun Pharmaceuticals Inc., San Diego, CA ITMN-191(R-7227) Antiviral serine protease InterMune inhibitor PharmaceuticalsInc., Brisbane, CA GL-59728 Antiviral NS5B Replicase Genelabs InhibitorANA-971 Antiviral TLR-7 agonist Anadys

The compounds of the present disclosure may also be used as laboratoryreagents. Compounds may be instrumental in providing research tools fordesigning of viral replication assays, validation of animal assaysystems and structural biology studies to further enhance knowledge ofthe HCV disease mechanisms. Further, the compounds of the presentdisclosure are useful in establishing or determining the binding site ofother antiviral compounds, for example, by competitive inhibition.

The compounds of this disclosure may also be used to treat or preventviral contamination of materials and therefore reduce the risk of viralinfection of laboratory or medical personnel or patients who come incontact with such materials, e.g., blood, tissue, surgical instrumentsand garments, laboratory instruments and garments, and blood collectionor transfusion apparatuses and materials.

This disclosure is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes includingthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

The abbreviations used in the present application, includingparticularly in the illustrative schemes and examples which follow, arewell-known to those skilled in the art. Some of the abbreviations usedare as follows: HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; Boc or BOC for tert-butoxycarbonyl; NBS forN-bromosuccinimide; tBu or t-Bu for tert-butyl; SEM for-(trimethylsilyl)ethoxymethyl; DMSO for dimethylsulfoxide; MeOH formethanol; TFA for trifluoroacetic acid; RT for room temperature orretention time (context will dictate); t_(R) for retention time; EDCIfor 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAPfor 4-dimethylaminopyridine; THF for tetrahydrofuran; DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; t-Bu; DEA for diethylamine; HMDS forhexamethyldisilazide; DMF for N,N-dimethylformamide; Bzl for benzyl;EtOH for ethanol; iPrOH or i-PrOH for isopropanol; Me₂S fordimethylsulfide; Et₃N or TEA for triethylamine; Ph for phenyl; OAc foracetate; EtOAc for ethyl acetate; dppf for1,1′-bis(diphenylphosphino)ferrocene; iPr₂EtN or DIPEA fordiisopropylethylamine; Cbz for carbobenzyloxy; n-BuLi forn-butyllithium; ACN for acetonitrile; h or hr for hours; m or min forminutes; s for seconds; LiHMDS for lithium hexamethyldisilazide; DIBALfor diisobutyl aluminum hydride; TBDMSCl for tert-butyldimethylsilylchloride; Me for methyl; ca. for about; OAc for acetate; iPr forisopropyl; Et for ethyl; Bn for benzyl; and HOAT for1-hydroxy-7-azabenzotriazole.

The abbreviations used in the present application, includingparticularly in the illustrative schemes and examples which follow, arewell-known to those skilled in the art. Some of the abbreviations usedare as follows:

The compounds and processes of the present disclosure will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the present disclosuremay be prepared. Starting materials can be obtained from commercialsources or prepared by well-established literature methods known tothose of ordinary skill in the art. It will be readily apparent to oneof ordinary skill in the art that the compounds defined above can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. It will also be readily apparent to oneskilled in the art that the selective protection and deprotection steps,as well as the order of the steps themselves, can be carried out invarying order, depending on the nature of the variables to successfullycomplete the syntheses below. The variables are as defined above unlessotherwise noted below.

Scheme 1 Symmetric or Asymmetric Biphenyls

Aryl halide 1 and boronic ester 2 can be coupled to produce biaryl 3using standard Suzuki-Miayura coupling conditions (Angew Chem. Int. Ed.Engl 2001, 40, 4544). It should be noted that the boronic acid analog of2 may be used in place of the ester. Mono-deprotection of thepyrrolidine moiety may be accomplished when R¹² and R¹³ are different.When R¹²=benzyl, and R¹³=t-butyl treatment to hydrogenolytic conditionsproduces 4. For example, Pd/C catalyst in the presence of a base such aspotassium carbonate can be used. Acylation of 4 can be accomplishedunder standard acylation conditions. A coupling reagent such as HATU incombination with an amine base such as Hunig's base can be used in thisregard. Alternatively, 4 may be reacted with an isocyanate or carbamoylchloride to provide compounds of formula 5 where R⁹ is an amine. Furtherdeprotection of 5 can be accomplished by treatment with strong acid suchas HCl or trifluoroacetic acid. Standard conditions analogous to thoseused to convert 4 to 5 can be used to prepare 7 from 6. In anotherembodiment where R¹²═R¹³=t-Bu, direct conversion to 8 can beaccomplished by treatment of 3 with strong acid such as HCl ortrifluoroacetic acid. Conversion of 8 to 7 is accomplished in analogousfashion to the methods used to prepare 5 from 4 or 7 from 6. In thisinstance however, the caps in 7 will be identical.

Scheme 2 Asymmetrically Capped Biphenyls

Conversion of 6 (from Scheme 1) to 10 can be done using standard amidecoupling conditions such as HATU with an amine base, such as Hunig'sbase. Deprotection can be accomplished with strong acid such as HCl ortrifluoroacetic acid affording 11. Compound 11 can then be converted to12, 13, or 14 using an acid chloride, an isocyanate or carbamoylchloride, or a chloroformate respectively.

Scheme 3 Symmetric Cap Elaborated Biphenyls

Compound 15 (15=7 (Scheme 1) wherein each R⁹ is —CH(NHBoc)R¹⁸) can beconverted to 16 via treatment with strong acid such as HCl ortrifluoroacetic acid. Compounds 17, 18, and 19 can be prepared from 16by treating 16 with an appropriate chloroformate, isocyanate orcarbamoyl chloride, or an acid chloride respectively.

Scheme 4 Symmetric Biphenyls

Symmetrical biphenyl analogs (compounds of formula 7 where both halvesof the molecule are equivalent) can be synthesized starting frombromoketone 20. Amination by displacement with a nucleophile such asazide, phthalimide or preferably sodium diformylamide (Yinglin andHongwen, Synthesis 1990, 122) followed by deprotection affords 21.Condensation under standard amination conditions such as HATU andHunig's base with an appropriately protected amino acid provides 22.Heating with ammonium acetate under thermal or microwave conditionsresults in the formation of 3 which can be deprotected with strong acidsuch as HCl or trifluoroacetic acid (R¹²═R¹³=t-Bu) or by hydrogenolysiswith hydrogen gas and a transition metal catalyst such asPd/C(R¹²═R¹³=benzyl). Acylation can be affected with a carboxylic acid(R⁹CO₂H) in a manner similar to the conversion of 21 to 22. Ureaformation can be accomplished by treatment with an appropriateisocycante (R⁹═R²⁴R²⁵N; R²⁵═H) or carbamoyl chloride (R⁹═R²⁴R²⁵N; R²⁵ isother than hydrogen).

Scheme 5 Starting Materials 25 and 2

Scheme 5 describes the preparation of some of the starting materialsrequired for the synthetic sequences depicted in Schemes 1-4. Keyintermediate 25 (analogous to 1 in Scheme 1) is prepared from keto-amide24 or keto-ester 27 via heating with ammonium acetate under thermal ormicrowave conditions. Keto-amide 24 can be prepared from 23 viacondensation with an appropriate cyclic or acyclic amino acid understandard amide formation conditions. Bromide 26 can give rise to 23 bytreatment with a nucleophile such as azide, phthalimide or sodiumdiformylamide (Synthesis 1990, 122) followed by deprotection. Bromide 26can also be converted to 27 by reacting with an appropriate cyclic oracyclic N-protected amino acid in the presence of base such as potassiumcarbonate or sodium bicarbonate. Bromination of 28 with a source ofbromonium ion such as bromine, NBS, or CBr₄ results in the formation of26. Bromide 25 can be converted to boronic ester 2 via treatment withbis-pinacalotodiboron under palladium catalysis according to the methoddescribed in Journal of Organic Chemistry 1995, 60, 7508, or variationsthereof.

Scheme 6 Starting Material 31a

In another embodiment, starting materials such as 31a (analogous to 25in Scheme 5 and 1 in Scheme 1) may be prepared by reactingbromoimidazole derivatives 31 under Suzuki-type coupling conditions witha variety of chloro-substituted aryl boronic acids which can either beprepared by standard methodologies (see, for example, Organic Letters2006, 8, 305 and references cited therein) or purchased from commercialsuppliers. Bromoimidazole 31 can be obtained by brominating imidazole 30with a source of bromonium ion such as bromine, CBr₄, orN-bromosuccinimide. Imidazole 30 can be prepared from N-protected aminoacids which are appropriately substituted by reacting with glyoxal in amethanolic solution of ammonium hydroxide.

Scheme 7 Heteroaryls

In yet another embodiment of the current disclosure, aryl halide 32 canbe coupled under Suzuki-Miyaura palladium catalyzed conditions to formthe heteroaryl derivative 34. Compound 34 can be elaborated to 35 bytreatment to hydrogenolytic conditions with hydrogen and a transitionmetal catalyst such as palladium on carbon (R¹³=benzyl). Acylation of 35can be accomplished with an appropriate acid chloride (R⁹COCl) in thepresence of a base such as triethylamine, with an appropriatelysubstituted carboxylic acid (R⁹CO₂H) in the presence of a standardcoupling reagent such as HATU, or with an isoscyanate (R²⁷NCO whereinR⁹═R²⁷R²⁸N—; R²⁸═H) or carbamoyl chloride (R²⁷R²⁸NCOCl whereinR⁹═R²⁷R²⁸N—). Compound 37 can be prepared from 36 (R¹²=t-Bu) viatreatment with strong acid such as HCl or trifluoroacetic acid.Acylation of the resulting amine in 37 to give 38 can be accomplished asin the transformation of 35 to 36. In cases where R¹²═R¹³, 34 can bedirectly transformed into 39 by treatment with strong acid such as HClor trifluoroacetic acid (R¹²═R¹³=t-Bu) or by employing hydrogenolyticconditions with hydrogen and a transition metal catalyst such aspalladium on carbon (R¹²═R¹³=benzyl). Acylation of 39 can beaccomplished in analogous fashion to that described for thetransformation of 35 to 36.

Scheme 8

Heteroaryl chloride 29 can be converted to symmetrical analog 40 viatreatment with a source of palladium such as dichlorobis(benzonitrile)palladium in the presence of tetrakis(dimethylamino)ethylene at elevatedtemperature. Removal of the SEM ether and Boc carbamates found in 40 canbe accomplished in one step by treatment with a strong acid such as HClor trifluoroacetic acid providing 41. Conversion to 42 can beaccomplished in similar fashion to the conditions used to convert 38 to39 in Scheme 7.

Scheme 9 Symmetric Cap Substituted Heteroaryls

Compound 43 (analogous to 42 wherein R₂₃=—CH(NHBoc)R₂₄) may beelaborated to 45, 46, and 47 via similar methodologies to thosedescribed in Scheme 3. In cases where R₂₀=alkoxymethyl (ie; SEM),removal can be accomplished simultaneously with removal of the Boccarbamate (cf; 43 to 44) using strong acid such as HCl ortrifluoroacetic acid.

Scheme 10 Starting Material 29

Heteroaryl bromides 54 may be reacted with a vinyl stannane such astributyl(1-ethoxyvinyl)tin in the presence of a source of palladium suchas dichlorobis(triphenylphosphine)palladium (II) to provide 55 which canbe subsequently transformed into bromoketone 51 via treatment with asource of bromonium ion such as N-bromosuccinimide, CBr₄, or bromine.Alternatively, keto-substituted heteroaryl bromides 53 may be directlyconverted to 51 via treatment with a source of bromonium ion such asbromine, CBr₄, or N-bromosuccinimide. Bromide 51 can be converted toaminoketone 48 via addition of sodium azide, potassium phthalimide orsodium diformylamide (Synthesis 1990 122) followed by deprotection.Aminoketone 48 can then be coupled with an appropriately substitutedamino acid under standard amide formation conditions (i.e.; a couplingreagent such as HATU in the presence of a mild base such as Hunig'sbase) to provide 49. Compound 49 can then be further transformed intoimidazole 50 via reacting with ammonium acetate under thermal ormicrowave conditions. Alternatively, 51 can be directly reacted with anappropriately substituted amino acid in the presence of a base such assodium bicarbonate or potassium carbonate providing 52 which can in turnbe reacted with ammonium acetate under thermal or microwave conditionsto provide 50. Imidazole 50 can be protected with an alkoxylmethyl groupby treatment with the appropriate alkoxymethyl halide such as2-(trimethylsilyl)ethoxymethyl chloride after first being deprotonatedwith a strong base such as sodium hydride.

Scheme 11 Substituted Phenylglycine Derivatives

Substituted phenylglycine derivatives can be prepared by a number ofmethods shown below. Phenylglycine t-butyl ester can be reductivelyalkylated (pathway A) with an appropriate aldehyde and a reductant suchas sodium cyanoborohydride in acidic medium. Hydrolysis of the t-butylester can be accomplished with strong acid such as HCl ortrifluoroacetic acid. Alternatively, phenylglycine can be alkylated withan alkyl halide such as ethyl iodide and a base such as sodiumbicarbonate or potassium carbonate (pathway B). Pathway C illustratesreductive alkylation of phenylglycine as in pathway A followed by asecond reductive alkylation with an alternate aldehyde such asformaldehyde in the presence of a reducing agent and acid. Pathway Dillustrates the synthesis of substituted phenylglycines via thecorresponding mandelic acid analogs. Conversion of the secondary alcoholto a competent leaving group can be accomplished with p-toluensulfonylchloride. Displacement of the tosylate group with an appropriate aminefollowed by reductive removal of the benzyl ester can providesubstituted phenylglycine derivatives. In pathway E a racemicsubstituted phenylglycine derivative is resolved by esterification withan enantiomerically pure chiral auxiliary such as but not limited to(+)-1-phenylethanol, (−)-1-phenylethanol, an Evan's oxazolidinone, orenantiomerically pure pantolactone. Separation of the diastereomers isaccomplished via chromatography (silica gel, HPLC, crystallization, etc)followed by removal of the chiral auxiliary providing enantiomericallypure phenylglycine derivatives. Pathway H illustrates a syntheticsequence which intersects with pathway E wherein the aforementionedchiral auxiliary is installed prior to amine addition. Alternatively, anester of an arylacetic acid can be brominated with a source of bromoniumion such as bromine, N-bromosuccinimide, or CBr₄. The resultant benzylicbromide can be displaced with a variety of mono- or disubstituted aminesin the presence of a tertiary amine base such as triethylamine orHunig's base. Hydrolysis of the methyl ester via treatment with lithiumhydroxide at low temperature or 6N HCl at elevated temperature providesthe substituted phenylglycine derivatives. Another method is shown inpathway G. Glycine analogs can be derivatized with a variety of arylhalides in the presence of a source of palladium (0) such as palladiumbis(tributylphosphine) and base such as potassium phosphate. Theresultant ester can then be hydrolyzed by treatment with base or acid.It should be understood that other well known methods to preparephenylglycine derivatives exist in the art and can be amended to providethe desired compounds in this description. It should also be understoodthat the final phenylglycine derivatives can be purified to enantiomericpurity greater than 98% ee via preparative HPLC.

Scheme 12 Acylated Amino Acid Derivatives

In another embodiment of the present disclosure, acylated phenylglycinederivatives may be prepared as illustrated below. Phenylglycinederivatives wherein the carboxylic acid is protected as an easilyremoved ester, may be acylated with an acid chloride in the presence ofa base such as triethylamine to provide the corresponding amides(pathway A). Pathway B illustrates the acylation of the startingphenylglycine derivative with an appropriate chloroformate while pathwayC shows reaction with an appropriate isocyanate or carbamoyl chloride.Each of the three intermediates shown in pathways A-C may be deprotectedby methods known by those skilled in the art (ie; treatment of thet-butyl ester with strong base such as HCl or trifluoroacetic acid).

Scheme 13

Amino-substituted phenylacetic acids may be prepared by treatment of achloromethylphenylacetic acid with an excess of an amine.

Compound Analysis Conditions

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters Micromass ZQ MS system. It shouldbe noted that retention times may vary slightly between machines. The LCconditions employed in determining the retention time (RT) were:

Condition 1

Column=Phenomenex-Luna 3.0×50 mm S10

Start % B=0

Final % B=100

Gradient time=2 min

Stop time=3 min

Flow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition 2

Column=Phenomenex-Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient time=2 min

Stop time=3 min

Flow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition 3

Column=HPLC XTERRA C18 3.0×50 mm S7

Start % B=0

Final % B=100

Gradient time=3 min

Stop time=4 min

Flow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition M1

Column: Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient time=3 min

Stop time=4 min

Flow rate=4 mL/min

Solvent A:=95% H₂O: 5% CH₃CN, 10 mm Ammonium acetate

Solvent B:=5% H₂O: 95% CH₃CN; 10 mm Ammonium acetate

Synthesis of Common Caps

A suspension of 10% Pd/C (2.0 g) in methanol (10 mL) was added to amixture of (R)-2-phenylglycine (10 g, 66.2 mmol), formaldehyde (33 mL of37% wt. in water), 1N HCl (30 mL) and methanol (30 mL), and exposed toH₂ (60 psi) for 3 hours. The reaction mixture was filtered throughdiatomaceous earth (Celite®), and the filtrate was concentrated invacuo. The resulting crude material was recrystallized from isopropanolto provide the HCl salt of Cap-1 as a white needle (4.0 g). Opticalrotation: −117.1° [c=9.95 mg/mL in H₂O; λ=589 nm]. ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz): δ 7.43-7.34 (m, 5H), 4.14 (s, 1H), 2.43 (s, 6H); LC(Cond. 1): RT=0.25; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.10.found 180.17; HRMS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.1025. found180.1017.

NaBH₃CN (6.22 g, 94 mmol) was added in portions over a few minutes to acooled (ice/water) mixture of (R)-2-Phenylglycine (6.02 g, 39.8 mmol)and MeOH (100 mL), and stirred for 5 min. Acetaldehyde (10 mL) was addeddrop-wise over 10 min and stirring was continued at the same cooledtemperature for 45 min and at ambient temperature for ˜6.5 hr. Thereaction mixture was cooled back with ice-water bath, treated with water(3 mL) and then quenched with a drop-wise addition of concentrated HClover ˜45 min until the pH of the mixture is ˜1.5-2.0. The cooling bathwas removed and the stirring was continued while adding concentrated HClin order to maintain the pH of the mixture around 1.5-2.0. The reactionmixture was stirred over night, filtered to remove the white suspension,and the filtrate was concentrated in vacuo. The crude material wasrecrystallized from ethanol to afford the HCl salt of Cap-2 as a shiningwhite solid in two crops (crop-1: 4.16 g; crop-2: 2.19 g). ¹H NMR(DMSO-d₆, δ=2.5 ppm, 400 MHz): 10.44 (1.00, br s, 1H), 7.66 (m, 2H),7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98 (br m, 2H), 1.20 (appbr s, 6H). Crop-1: [α]²⁵-102.21° (c=0.357, H₂O); crop-2: [α]²⁵-99.7°(c=0.357, H₂O). LC (Cond. 1): RT=0.43 min; LC/MS: Anal. Calcd. for[M+H]⁺ C₁₂H₁₈NO₂: 208.13. found 208.26

Acetaldehyde (5.0 mL, 89.1 mmol) and a suspension of 10% Pd/C (720 mg)in methanol/H₂O (4 mL/1 mL) was sequentially added to a cooled (˜15° C.)mixture of (R)-2-phenylglycine (3.096 g, 20.48 mmol), 1N HCl (30 mL) andmethanol (40 mL). The cooling bath was removed and the reaction mixturewas stirred under a balloon of H₂ for 17 hours. An additionalacetaldehyde (10 mL, 178.2 mmol) was added and stirring continued underH₂ atmosphere for 24 hours [Note: the supply of H₂ was replenished asneeded throughout the reaction]. The reaction mixture was filteredthrough diatomaceous earth (Celite®), and the filtrate was concentratedin vacuo. The resulting crude material was recrystallized fromisopropanol to provide the HCl salt of (R)-2-(ethylamino)-2-phenylaceticacid as a shining white solid (2.846 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400MHz): δ 14.15 (br s, 1H), 9.55 (br s, 2H), 7.55-7.48 (m, 5H), 2.88 (brm, 1H), 2.73 (br m, 1H), 1.20 (app t, J=7.2, 3H). LC (Cond. 1): RT=0.39min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂:180.10. found 180.18.

A suspension of 10% Pd/C (536 mg) in methanol/H₂O (3 mL/1 mL) was addedto a mixture of (R)-2-(ethylamino)-2-phenylacetic acid/HCl (1.492 g,6.918 mmol), formaldehyde (20 mL of 37% wt. in water), 1N HCl (20 mL)and methanol (23 mL). The reaction mixture was stirred under a balloonof H₂ for ˜72 hours, where the H₂ supply was replenished as needed. Thereaction mixture was filtered through diatomaceous earth (Celite®) andthe filtrate was concentrated in vacuo. The resulting crude material wasrecrystallized from isopropanol (50 mL) to provide the HCl salt of Cap-3as a white solid (985 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 10.48(br s, 1H), 7.59-7.51 (m, 5H), 5.26 (s, 1H), 3.08 (app br s, 2H), 2.65(br s, 3H), 1.24 (br m, 3H). LC (Cond. 1): RT=0.39 min; >95% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.12. found 194.18;HRMS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.1180. found 194.1181.

ClCO₂Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water)THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl(9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol)over 6 min, and stirred at similar temperature for 5.5 hours. Thevolatile component was removed in vacuo, and the residue was partitionedbetween water (100 mL) and ethyl acetate (200 mL). The organic layer waswashed with 1N HCl (25 mL) and saturated NaHCO₃ solution (30 mL), dried(MgSO₄), filtered, and concentrated in vacuo. The resultant colorlessoil was triturated from hexanes, filtered and washed with hexanes (100mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetateas a white solid (7.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.98 (d,J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s,9H). LC (Cond. 1): RT=1.53 min; ˜90% homogeneity index; LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₄H₁₉NNaO₄: 288.12. found 288.15.

TFA (16 mL) was added dropwise to a cooled (ice/water) CH₂Cl₂ (160 mL)solution of the above product over 7 minutes, and the cooling bath wasremoved and the reaction mixture was stirred for 20 hours. Since thedeprotection was still not complete, an additional TFA (1.0 mL) wasadded and stirring continued for an additional 2 hours. The volatilecomponent was removed in vacuo, and the resulting oil residue wastreated with diethyl ether (15 mL) and hexanes (12 mL) to provide aprecipitate. The precipitate was filtered and washed with diethylether/hexanes (˜1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 asa fluffy white solid (5.57 g). Optical rotation: −176.9° [c=3.7 mg/mL inH₂O; λ=589 nm]. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.84 (br s,1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55(s, 3H). LC (Cond. 1): RT=1.01 min; >95% homogeneity index; LC/MS: Anal.Calcd. for [M+H]⁺ C₁₀H₁₂NO₄ 210.08. found 210.17; HRMS: Anal. Calcd. for[M+H]⁺ C₁₀H₁₂NO₄ 210.0766. found 210.0756.

A mixture of (R)-2-phenylglycine (1.0 g, 6.62 mmol), 1,4-dibromobutane(1.57 g, 7.27 mmol) and Na₂CO₃ (2.10 g, 19.8 mmol) in ethanol (40 mL)was heated at 100° C. for 21 hours. The reaction mixture was cooled toambient temperature and filtered, and the filtrate was concentrated invacuo. The residue was dissolved in ethanol and acidified with 1N HCl topH 3-4, and the volatile component was removed in vacuo. The resultingcrude material was purified by a reverse phase HPLC (water/methanol/TFA)to provide the TFA salt of Cap-5 as a semi-viscous white foam (1.0 g).¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 10.68 (br s, 1H), 7.51 (m, 5H), 5.23(s, 1H), 3.34 (app br s, 2H), 3.05 (app br s, 2H), 1.95 (app br s, 4H);RT=0.30 min (Cond. 1); >98% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺ C₁₂H₁₆NO₂: 206.12. found 206.25.

The TFA salt of Cap-6 was synthesized from (R)-2-phenylglycine and1-bromo-2-(2-bromoethoxy)ethane by using the method of preparation ofCap-5. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.20 (br s, 1H), 7.50 (m,5H), 4.92 (s, 1H), 3.78 (app br s, 4H), 3.08 (app br s, 2H), 2.81 (appbr s, 2H); RT=0.32 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M+H]⁺C₁₂H₁₆NO₃: 222.11. found 222.20; HRMS: Anal. Calcd. for [M+H]⁺C₁₂H₁₆NO₃: 222.1130. found 222.1121.

A CH₂Cl₂ (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4mmol) was added dropwise to a cooled (−5° C.) CH₂Cl₂ (200 mL) solutionof (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol),triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g,4.13 mmol), while maintaining the temperature between −5° C. and 0° C.The reaction was stirred at 0° C. for 9 hours, and then stored in afreezer (−25° C.) for 14 hours. It was allowed to thaw to ambienttemperature and washed with water (200 mL), 1N HCl (100 mL) and brine(100 mL), dried (MgSO₄), filtered, and concentrated in vacuo to providebenzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidifiedupon standing (16.5 g). The chiral integrity of the product was notchecked and that product was used for the next step without furtherpurification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H),7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H),5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Cond. 3); >90% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₂H₂₀NaO₅S: 419.09. found 419.04.

A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g,15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) andN,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for7 hours. The reaction was allowed to cool to ambient temperature and thevolatile component was removed in vacuo. The residue was partitionedbetween ethylacetate and water, and the organic layer was washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting crude material was purified by flash chromatography (silicagel, ethyl acetate) to provide benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscousoil (4.56 g). Chiral HPLC analysis (Chiralcel OD-H) indicated that thesample is a mixture of enantiomers in a 38.2 to 58.7 ratio. Theseparation of the enantiomers were effected as follow: the product wasdissolved in 120 mL of ethanol/heptane (1:1) and injected (5mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at220 nm. Enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) wereretrieved as viscous oil. ¹H NMR (CDCl₃, δ=7.26, 500 MHz) 7.44-7.40 (m,2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08(d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H).RT=2.10 (Cond. 3); >98% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺ C₂₀H₂₅N₂O₂: 325.19. found 325.20.

A methanol (10 mL) solution of either enantiomer of benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate (1.0 g, 3.1 mmol) was addedto a suspension of 10% Pd/C (120 mg) in methanol (5.0 mL). The reactionmixture was exposed to a balloon of hydrogen, under a carefulmonitoring, for <50 min. Immediately after the completion of thereaction, the catalyst was filtered through diatomaceous earth (Celite®)and the filtrate was concentrated in vacuo to provide Cap-7,contaminated with phenylacetic acid as a tan foam (867.6 mg; mass isabove the theoretical yield). The product was used for the next stepwithout further purification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H), 3.92 (s, 1H), 2.63-2.48 (app. bs,2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT=0.31 (Cond. 2); >90%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.14.found 235.15; HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.1447. found235.1440.

The synthesis of Cap-8 and Cap-9 was conducted according to thesynthesis of Cap-7 by using appropriate amines for the SN₂ displacementstep (i.e., 4-hydroxypiperidine for Cap-8 and (S)-3-fluoropyrrolidinefor Cap-9) and modified conditions for the separation of the respectivestereoisomeric intermediates, as described below.

The enantiomeric separation of the intermediate benzyl2-(4-hydroxypiperidin-1-yl)-2-phenyl acetate was effected by employingthe following conditions: the compound (500 mg) was dissolved inethanol/heptane (5 mL/45 mL). The resulting solution was injected (5mL/injection) on a chiral HPLC column (Chiracel OJ, 2 cm ID×25 cm L, 10μm) eluting with 80:20 heptane/ethanol at 10 mL/min, monitored at 220nm, to provide 186.3 mg of enantiomer-1 and 209.1 mg of enantiomer-2 aslight-yellow viscous oils. These benzyl ester was hydrogenolysedaccording to the preparation of Cap-7 to provide Cap-8: ¹H NMR (DMSO-d₆,δ=2.5, 500 MHz) 7.40 (d, J=7, 2H), 7.28-7.20 (m, 3H), 3.78 (s 1H), 3.46(m, 1H), 2.93 (m, 1H), 2.62 (m, 1H), 2.20 (m, 2H), 1.70 (m, 2H), 1.42(m, 2H). RT=0.28 (Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C₁₃H₁₈NO₃: 236.13. found 236.07; HRMS: Calcd. for [M+H]⁺C₁₃H₁₈NO₃: 236.1287. found 236.1283.

The diastereomeric separation of the intermediate benzyl2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetate was effected byemploying the following conditions: the ester (220 mg) was separated ona chiral HPLC column (Chiracel OJ-H, 0.46 cm ID×25 cm L, 5 μm) elutingwith 95% CO₂/5% methanol with 0.1% TFA, at 10 bar pressure, 70 mL/minflow rate, and a temperature of 35° C. The HPLC elute for the respectivestereoisomers was concentrated, and the residue was dissolved in CH₂Cl₂(20 mL) and washed with an aqueous medium (10 mL water+1 mL saturatedNaHCO₃ solution). The organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo to provide 92.5 mg of fraction-1 and 59.6 mg offraction-2. These benzyl esters were hydrogenolysed according to thepreparation of Cap-7 to prepare Caps 9a and 9b. Cap-9a (diastereomer-1;the sample is a TFA salt as a result of purification on a reverse phaseHPLC using H₂O/methanol/TFA solvent): ¹H NMR (DMSO-d₆, δ=2.5, 400 MHz)7.55-7.48 (m, 5H), 5.38 (d of m, J=53.7, 1H), 5.09 (br s, 1H), 3.84-2.82(br m, 4H), 2.31-2.09 (m, 2H). RT=0.42 (Cond. 1); >95% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂: 224.11. found 224.14;Cap-9b (diastereomer-2): ¹H NMR (DMSO-d₆, δ=2.5, 400 MHz) 7.43-7.21 (m,5H), 5.19 (d of m, J=55.9, 1H), 3.97 (s, 1H), 2.95-2.43 (m, 4H),2.19-1.78 (m, 2H). RT=0.44 (Cond. 1); LC/MS: Anal. Calcd. for [M+H]⁺C₁₂H₁₅FNO₂: 224.11. found 224.14.

To a solution of D-proline (2.0 g, 17 mmol) and formaldehyde (2.0 mL of37% wt. in H₂O) in methanol (15 mL) was added a suspension of 10% Pd/C(500 mg) in methanol (5 mL). The mixture was stirred under a balloon ofhydrogen for 23 hours. The reaction mixture was filtered throughdiatomaceous earth (Celite®) and concentrated in vacuo to provide Cap-10as an off-white solid (2.15 g). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) 3.42(m, 1H), 3.37 (dd, J=9.4, 6.1, 1H), 2.85-2.78 (m, 1H), 2.66 (s, 3H),2.21-2.13 (m, 1H), 1.93-1.84 (m, 2H), 1.75-1.66 (m, 1H). RT=0.28 (Cond.2); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₆H₁₂NO₂:130.09. found 129.96.

A mixture of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8mmol), formaldehyde (0.5 mL of 37% wt. in H₂O), 12 N HCl (0.25 mL) and10% Pd/C (50 mg) in methanol (20 mL) was stirred under a balloon ofhydrogen for 19 hours. The reaction mixture was filtered throughdiatomaceous earth (Celite®) and the filtrate was concentrated in vacuo.The residue was recrystallized from isopropanol to provide the HCl saltof Cap-11 as a white solid (337.7 mg). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz)5.39 (d m, J=53.7, 1H), 4.30 (m, 1H), 3.90 (ddd, J=31.5, 13.5, 4.5, 1H),3.33 (dd, J=25.6, 13.4, 1H), 2.85 (s, 3H), 2.60-2.51 (m, 1H), 2.39-2.26(m, 1H). RT=0.28 (Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C₆H₁₁FNO₂: 148.08. found 148.06.

L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodiumcarbonate solution (50 mL), and a THF (50 mL) solution of methylchloroformate (4.0 mL) was added to it. The reaction mixture was stirredunder ambient conditions for 4.5 hours and concentrated in vacuo. Theresulting white solid was dissolved in water and acidified with 1N HClto a pH˜2-3. The resulting solutions was extracted with ethyl acetate(3×100 mL), and the combined organic phase was dried (Na₂SO₄), filtered,and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg ofthis material was purified by a reverse phase HPLC (H₂O/methanol/TFA) toprovide 150 mg of Cap-12 as a colorless oil. ¹H NMR (DMSO-d₆, δ=2.5, 500MHz) 7.44 (d, J=7.3, 0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s,3H), 1.25 (d, J=7.3, 3H).

A mixture of L-alanine (2.5 g, 28 mmol), formaldehyde (8.4 g, 37 wt. %),1N HCl (30 mL) and 10% Pd/C (500 mg) in methanol (30 mL) was stirredunder a hydrogen atmosphere (50 psi) for 5 hours. The reaction mixturewas filtered through diatomaceous earth (Celite®) and the filtrate wasconcentrated in vacuo to provide the HCl salt of Cap-13 as an oil whichsolidified upon standing under vacuum (4.4 g; the mass is abovetheoretical yield). The product was used without further purification.¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.1 (br s, 1H), 4.06 (q, J=7.4, 1H),2.76 (s, 6H), 1.46 (d, J=7.3, 3H).

Step 1: A mixture of (R)-(−)-D-phenylglycine tert-butyl ester (3.00 g,12.3 mmol), NaBH₃CN (0.773 g, 12.3 mmol), KOH (0.690 g, 12.3 mmol) andacetic acid (0.352 mL, 6.15 mmol) were stirred in methanol at 0° C. Tothis mixture was added glutaric dialdehyde (2.23 mL, 12.3 mmol) dropwiseover 5 minutes. The reaction mixture was stirred as it was allowed towarm to ambient temperature and stirring was continued at the sametemperature for 16 hours. The solvent was subsequently removed and theresidue was partitioned with 10% aqueous NaOH and ethyl acetate. Theorganic phase was separated, dried (MgSO₄), filtered and concentrated todryness to provide a clear oil. This material was purified byreverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA) to give the intermediate ester (2.70 g, 56%) as aclear oil. ¹HNMR (400 MHz, CDCl₃) δ 7.53-7.44 (m, 3H), 7.40-7.37 (m,2H), 3.87 (d, J=10.9 Hz, 1H), 3.59 (d, J=10.9 Hz, 1H), 2.99 (t, J=11.2Hz, 1H), 2.59 (t, J=11.4 Hz, 1H), 2.07-2.02 (m, 2H), 1.82 (d, J=1.82 Hz,3H), 1.40 (s, 9H). LC/MS: Anal. Calcd. for C₁₇H₂₅NO₂: 275. found: 276(M+H)⁺.

Step 2: To a stirred solution of the intermediate ester (1.12 g, 2.88mmol) in dichloromethane (10 mL) was added TFA (3 mL). The reactionmixture was stirred at ambient temperature for 4 hours and then it wasconcentrated to dryness to give a light yellow oil. The oil was purifiedusing reverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA). The appropriate fractions were combined andconcentrated to dryness in vacuo. The residue was then dissolved in aminimum amount of methanol and applied to applied to MCX LP extractioncartridges (2×6 g). The cartridges were rinsed with methanol (40 mL) andthen the desired compound was eluted using 2M ammonia in methanol (50mL). Product-containing fractions were combined and concentrated and theresidue was taken up in water. Lyophilization of this solution providedthe title compound (0.492 g, 78%) as a light yellow solid. ¹HNMR(DMSO-d₆) δ 7.50 (s, 5H), 5.13 (s, 1H), 3.09 (br s, 2H), 2.92-2.89 (m,2H), 1.74 (m, 4H), 1.48 (br s, 2H). LC/MS: Anal. Calcd. for C₁₃H₁₇NO₂:219. found: 220 (M+H)⁺.

Step 1; (S)-1-Phenylethyl 2-bromo-2-phenylacetate: To a mixture ofα-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol(7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane(100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. Theresulting solution was stirred at room temperature under Ar for 18 hoursand then it was diluted with ethyl acetate, washed (H₂O×2, brine), dried(Na₂SO₄), filtered, and concentrated to give a pale yellow oil. Flashchromatography (SiO₂/hexane-ethyl acetate, 4:1) of this oil provided thetitle compound (11.64 g, 73%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz, 0.5H),5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51 (d, J=6.6Hz, 1.5H).

Step 2; (S)-1-Phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate: To a solutionof (S)-1-phenylethyl 2-bromo-2-phenylacetate (0.464 g, 1.45 mmol) in THF(8 mL) was added triethylamine (0.61 mL, 4.35 mmol), followed bytetrabutylammonium iodide (0.215 g, 0.58 mmol). The reaction mixture wasstirred at room temperature for 5 minutes and then a solution of4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) wasadded. The mixture was stirred for 1 hour at room temperature and thenit was heated at 55-60° C. (oil bath temperature) for 4 hours. Thecooled reaction mixture was then diluted with ethyl acetate (30 mL),washed (H₂O×2, brine), dried (MgSO₄), filtered and concentrated. Theresidue was purified by silica gel chromatography (0-60% ethylacetate-hexane) to provide first the (S,R)-isomer of the title compound(0.306 g, 60%) as a white solid and then the corresponding (S,S)-isomer(0.120 g, 23%), also as a white solid. (S,R)-isomer: ¹HNMR (CD₃OD) δ7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6 Hz, 1H), 4.05 (s,1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d,J=6.6 Hz, 3H), 1.18 (s, 3H). LCMS: Anal. Calcd. for C₂₂H₂₇NO₃: 353.found: 354 (M+H)⁺. (S,S)-isomer: ¹HNMR (CD₃OD) δ 7.41-7.30 (m, 5H),7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s,1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H),1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.20 (s,3H). LCMS: Anal. Calcd. for C₂₂H₂₇NO₃: 353. found: 354 (M+H)⁺.

Step 3; (R)-2-(4-Hydroxy-4-methylpiperidin-1-yl)-2-phenylacetic acid: Toa solution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate (0.185 g, 0.52mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL)and the mixture was stirred at room temperature for 2 hours. Thevolatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a palebluish solid (0.128 g, 98%). LCMS: Anal. Calcd. for C₁₄H₁₉NO₃: 249.found: 250 (M+H)⁺.

Step 1; (S)-1-Phenylethyl 2-(2-fluorophenyl)acetate: A mixture of2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-1-phenylethanol (5.62g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) inCH₂Cl₂ (100 mL) was stirred at room temperature for 12 hours. Thesolvent was then concentrated and the residue partitioned with H₂O-ethylacetate. The phases were separated and the aqueous layer back-extractedwith ethyl acetate (2×). The combined organic phases were washed (H₂O,brine), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (Biotage/0-20% ethylacetate-hexane) to provide the title compound as a colorless oil (8.38g, 92%). ¹HNMR (400 MHz, CD₃OD) δ 7.32-7.23 (m, 7H), 7.10-7.04 (m, 2),5.85 (q, J=6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J=6.5 Hz, 3H).

Step 2; (R)—((S)-1-Phenylethyl)2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate: To a solution of(S)-1-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4 mmol) in THF(1200 mL) at 0° C. was added DBU (6.19 g, 40.7 mmol) and the solutionwas allowed to warm to room temperature while stirring for 30 minutes.The solution was then cooled to −78° C. and a solution of CBr₄ (13.5 g,40.7 mmol) in THF (100 mL) was added and the mixture was allowed to warmto −10° C. and stirred at this temperature for 2 hours. The reactionmixture was quenched with saturated aq. NH₄Cl and the layers wereseparated. The aqueous layer was back-extracted with ethyl acetate (2×)and the combined organic phases were washed (H₂O, brine), dried(Na₂SO₄), filtered, and concentrated in vacuo. To the residue was addedpiperidine (5.73 mL, 58.1 mmol) and the solution was stirred at roomtemperature for 24 hours. The volatiles were then concentrated in vacuoand the residue was purified by silica gel chromatography (Biotage/0-30%diethyl ether-hexane) to provide a pure mixture of diastereomers (2:1ratio by ¹HNMR) as a yellow oil (2.07 g, 31%), along with unreactedstarting material (2.53 g, 51%). Further chromatography of thediastereomeric mixture (Biotage/0-10% diethyl ether-toluene) providedthe title compound as a colorless oil (0.737 g, 11%). ¹HNMR (400 MHz,CD₃OD) δ 7.52 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 7.33-7.40 (m, 1), 7.23-7.23(m, 4H), 7.02-7.23 (m, 4H), 5.86 (q, J=6.6 Hz, 1H), 4.45 (s, 1H),2.39-2.45 (m, 4H), 1.52-1.58 (m, 4H), 1.40-1.42 (m, 1H), 1.38 (d, J=6.6Hz, 3H). LCMS: Anal. Calcd. for C₂₁H₂₄FNO₂: 341. found: 342 (M+H)⁺.

Step 3; (R)-2-(2-fluorophenyl)-2-(piperidin-1-yl)acetic acid: A mixtureof (R)—((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate(0.737 g, 2.16 mmol) and 20% Pd(OH)₂/C (0.070 g) in ethanol (30 mL) washydrogenated at room temperature and atmospheric pressure (H₂ balloon)for 2 hours. The solution was then purged with Ar, filtered throughdiatomaceous earth (Celite®), and concentrated in vacuo. This providedthe title compound as a colorless solid (0.503 g, 98%). ¹HNMR (400 MHz,CD₃OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H),7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H).LCMS: Anal. Calcd. for C₁₃H₁₆FNO₂: 237. found: 238 (M+H)⁺.

Step 1; (S)-1-Phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate: To a solutionof (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF(25 mL) was added triethylamine (1.31 mL, 9.42 mmol), followed bytetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture wasstirred at room temperature for 5 minutes and then a solution of4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) wasadded. The mixture was stirred for 16 hours and then it was diluted withethyl acetate (100 mL), washed (H₂O 2, brine), dried (MgSO₄), filteredand concentrated. The residue was purified on a silica gel column (0-60%ethyl acetate-hexane) to provide an approximately 2:1 mixture ofdiastereomers, as judged by ¹HNMR. Separation of these isomers wasperformed using supercritical fluid chromatography (Chiralcel OJ-H,30×250 mm; 20% ethanol in CO₂ at 35° C.), to give first the (R)-isomerof the title compound (0.534 g, 27%) as a yellow oil and then thecorresponding (S)-isomer (0.271 g, 14%), also as a yellow oil.(S,R)-isomer: ¹HNMR (400 MHz, CD₃OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m,10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72(m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt,J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10 (dt, J=12.1,4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H). LCMS: Anal.Calcd. for C₂₇H₂₉NO₃: 415. found: 416 (M+H)⁺; (S,S)-isomer: ¹HNMR (400MHz, CD₃OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H),7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s,1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H), 2.57-2.52 (m,1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6 Hz, 1H), 2.12(dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H), 1.64 (dd,J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. forC₂₇H₂₉NO₃: 415. found: 416 (M+H)⁺.

The following esters were prepared in similar fashion employing step 1in the synthesis of Cap-17.

Intermediate- 17a

Diastereomer 1: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J = 6.41 Hz, 3H) 2.23-2.51 (m, 4 H) 3.35 (s, 4 H) 4.25 (s, 1 H) 5.05 (s, 2 H) 5.82 (d,J = 6.71 Hz, 1 H) 7.15-7.52 (m, 15 H). LCMS: Anal. Calcd. for:C₂₈H₃₀N₂O₄ 458.55; Found: 459.44 (M + H)⁺. Diastereomer 2: ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.45 (d, J = 6.71 Hz, 3 H) 2.27-2.44 (m, 4 H) 3.39(s, 4 H) 4.23 (s, 1 H) 5.06 (s, 2 H) 5.83 (d, J = 6.71 Hz, 1 H) 7.12(dd, J = 6.41, 3.05 Hz, 2 H) 7.19-7.27 (m, 3 H) 7.27-7.44 (m, 10 H).LCMS: Anal. Calcd. for: C₂₈H₃₀N₂O₄ 458.55; Found: 459.44 (M + H)⁺.Intermediate- 17b

Diastereomer 1: RT = 11.76 min (Cond'n II); LCMS: Anal. Calcd. for:C₂₀H₂₂N₂O₃ 338.4 Found: 339.39 (M + H)⁺; Diastereomer 2: RT = 10.05 min(Cond'n II); LCMS: Anal. Calcd. for: C₂₀H₂₂N₂O₃ 338.4; Found: 339.39(M + H)⁺. Intermediate- 17c

Diastereomer 1: T_(R) = 4.55 min (Cond'n I); LCMS: Anal. Calcd. for:C₂₁H₂₆N₂O₂ 338.44 Found: 339.45 (M + H)⁺; Diastereomer 2: T_(R) = 6.00min (Cond'n I); LCMS: Anal. Calcd. for: C₂₁H₂₆N₂O₂ 338.44 Found: 339.45(M + H)⁺. Intermediate- 17d

Diastereomer 1: RT = 7.19 min (Cond'n I); LCMS: Anal. Calcd. for:C₂₇H₂₉NO₂ 399.52 Found: 400.48 (M + H)⁺; Diastereomer 2: RT = 9.76 min(Cond'n I); LCMS: Anal. Calcd. for: C₂₇H₂₉NO₂ 399.52 Found: 400.48 (M +H)⁺.Chiral SFC Conditions for Determining Retention Time for Intermediates17b-17dCondition 1Column: Chiralpak AD-H Column, 4.6×250 mm, 5 μmSolvents: 90% CO₂—10% methanol with 0.1% DEATemp: 35° C.Pressure: 150 barFlow rate: 2.0 mL/min.UV monitored @220 nmInjection: 1.0 mg/3 mL methanolCondition 2Column: Chiralcel OD-H Column, 4.6×250 mm, 5 μmSolvents: 90% CO₂—10% methanol with 0.1% DEATemp: 35° C.Pressure: 150 barFlow rate: 2.0 mL/min.UV monitored @220 nmInjection: 1.0 mg/mL methanol

Cap-17, Step 2; (R)-2-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-phenylaceticacid: To a solution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate (0.350 g, 0.84mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL)and the mixture was stirred at room temperature for 2 hours. Thevolatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a whitesolid (0.230 g, 88%). LCMS: Anal. Calcd. for C₁₉H₂₁NO₃: 311. found: 312(M+H)⁺.

The following carboxylic acids were prepared in a similar fashion:

Cap- 17a

RT = 2.21 (Cond'n II); ¹H NMR (500 MHz, DMSO- d₆) δ ppm 2.20-2.35(m, 2H) 2.34-2.47(m, 2 H) 3.37(s, 4 H) 3.71(s, 1 H) 5.06(s, 2 H) 7.06-7.53(m,10 H). LCMS: Anal. Calcd. for: C₂₀H₂₂N₂O₄ 354.40; Found: 355.38 (M +H)⁺. Cap- 17b

RT = 0.27 (Cond'n III); LCMS: Anal. Calcd. for: C₁₂H₁₄N₂O₃ 234.25;Found: 235.22 (M + H)⁺. Cap- 17c

RT = 0.48 (Cond'n II); LCMS: Anal. Calcd. for: C₁₃N₁₈N₂O₂ 234.29; Found:235.31 (M + H)⁺. Cap- 17d

RT = 2.21 (Cond'n I); LCMS: Anal. Calcd. for; C₁₉H₂₁NO₂ 295.38; Found:296.33 (M + H)⁺.LCMS Conditions for Determining Retention Time for Caps 17a-17dCondition 1Column: Phenomenex-Luna 4.6×50 mm S10Start % B=0Final % B=100Gradient Time=4 minFlow Rate=4 mL/minWavelength=220Solvent A=10% methanol—90% H₂O—0.1% TFASolvent B=90% methanol—10% H₂O—0.1% TFACondition 2Column: Waters-Sunfire 4.6×50 mm S5Start % B=0Final % B=100Gradient Time=2 minFlow Rate=4 mL/minWavelength=220Solvent A=10% methanol—90% H₂O—0.1% TFASolvent B=90% methanol—10% H₂O—0.1% TFACondition 3Column: Phenomenex 10μ 3.0×50 mmStart % B=0Final % B=100Gradient Time=2 minFlow Rate=4 mL/minWavelength=220Solvent A=10% methanol—90% H₂O—0.1% TFASolvent B=90% methanol—10% H₂O—0.1% TFA

Step 1; (R,S)-Ethyl 2-(4-pyridyl)-2-bromoacetate: To a solution of ethyl4-pyridylacetate (1.00 g, 6.05 mmol) in dry THF (150 mL) at 0° C. underargon was added DBU (0.99 mL, 6.66 mmol). The reaction mixture wasallowed to warm to room temperature over 30 minutes and then it wascooled to −78° C. To this mixture was added CBr₄ (2.21 g, 6.66 mmol) andstirring was continued at −78° C. for 2 hours. The reaction mixture wasthen quenched with sat. aq. NH₄Cl and the phases were separated. Theorganic phase was washed (brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting yellow oil was immediately purifiedby flash chromatography (SiO₂/hexane-ethyl acetate, 1:1) to provide thetitle compound (1.40 g, 95%) as a somewhat unstable yellow oil. ¹HNMR(400 MHz, CDCl₃) δ 8.62 (dd, J=4.6, 1.8 Hz, 2H), 7.45 (dd, J=4.6, 1.8Hz, 2H), 5.24 (s, 1H), 4.21-4.29 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LCMS:Anal. Calcd. for C₉H₁₀BrNO₂: 242, 244. found: 243, 245 (M+H)⁺.

Step 2; (R,S)-Ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate: To asolution of (R,S)-ethyl 2-(4-pyridyl)-2-bromoacetate (1.40 g, 8.48 mmol)in DMF (10 mL) at room temperature was added dimethylamine (2M in THF,8.5 mL, 17.0 mmol). After completion of the reaction (as judged by tlc)the volatiles were removed in vacuo and the residue was purified byflash chromatography (Biotage, 40+M SiO₂ column; 50%-100% ethylacetate-hexane) to provide the title compound (0.539 g, 31%) as a lightyellow oil. ¹HNMR (400 MHz, CDCl₃) δ 8.58 (d, J=6.0 Hz, 2H), 7.36 (d,J=6.0 Hz, 2H), 4.17 (m, 2H), 3.92 (s, 1H), 2.27 (s, 6H), 1.22 (t, J=7.0Hz). LCMS: Anal. Calcd. for C₁₁H₁₆N₂O₂: 208. found: 209 (M+H)⁺.

Step 3; (R,S)-2-(4-Pyridyl)-2-(N,N-dimethylamino)acetic acid: To asolution of (R,S)-ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate(0.200 g, 0.960 mmol) in a mixture of THF-methanol-H₂O (1:1:1, 6 mL) wasadded powdered LiOH (0.120 g, 4.99 mmol) at room temperature. Thesolution was stirred for 3 hours and then it was acidified to pH 6 using1N HCl. The aqueous phase was washed with ethyl acetate and then it waslyophilized to give the dihydrochloride of the title compound as ayellow solid (containing LiCl). The product was used as such insubsequent steps. ¹HNMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.7 Hz, 2H),7.34 (d, J=5.7 Hz, 2H), 3.56 (s, 1H), 2.21 (s, 6H).

The following examples were prepared in similar fashion using the methoddescribed in Example 4;

Cap- 19

LCMS: Anal. Calcd. for C₉H₁₂N₂O₂: 180; found: 181(M + H)⁺. Cap- 20

LCMS: no ionization. ¹HNMR(400 MHz, CD₃OD) δ 8.55(d, J = 4.3 Hz, 1 H),7.84(app t, J = 5.3 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.37(app t, J =5.3 Hz, 1 H), 4.35(s, 1 H), 2.60(s, 6 H). Cap- 21

LCMS: Anal. Calcd. for C₉H_(11Cl)N₂O₂: 214, 216; found: 215, 217(M +H)⁺. Cap- 22

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225(M + H)⁺. Cap- 23

LCMS: Anal. Calcd. for C₁₄H₁₅NO₂: 247; found: 248(M + H)⁺. Cap- 24

LCMS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248(M + H)⁺. Cap- 25

LCMS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248(M + H)⁺. Cap- 26

LCMS: Anal. Calcd. for C₁₀H₁₂FNO₂: 247; found: 248(M + H)⁺. Cap- 27

LCMS: Anal. Calcd. for C₁₀H₁₂FNO₂: 247; found: 248(M + H)⁺. Cap- 28

LCMS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213, 215; found: 214, 217(M + H)⁺.Cap- 29

LCMS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213, 215; found: 214, 217(M + H)⁺.Cap- 30

LCMS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213, 215; found: 214, 217(M + H)⁺.Cap- 31

LCMS: Anal. Calcd. for C₈H₁₁N₂O₂S: 200; found: 201(M + H)⁺. Cap- 32

LCMS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186(M + H)⁺. Cap- 33

LCMS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186(M + H)⁺. Cap- 34

LCMS: Anal. Calcd. for C₁₁H₁₂N₂O₃: 220; found: 221(M + H)⁺. Cap- 35

LCMS: Anal. Calcd. for C₁₂H₁₃NO₂S: 235; found: 236(M + H)⁺. Cap- 36

LCMS: Anal. Calcd. for C₁₂H₁₄N₂O₂S: 250; found: 251(M + H)⁺.

Step 1; (R,S)-Ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)-acetate: Amixture of ethyl N,N-dimethylaminoacetate (0.462 g, 3.54 mmol), K₃PO₄(1.90 g, 8.95 mmol), Pd(t-Bu₃P)₂ (0.090 g, 0.176 mmol) and toluene (10mL) was degassed with a stream of Ar bubbles for 15 minutes. Thereaction mixture was then heated at 100° C. for 12 hours, after which itwas cooled to room temperature and poured into H₂O. The mixture wasextracted with ethyl acetate (2×) and the combined organic phases werewashed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified first by reverse-phase preparative HPLC(Primesphere C-18, 30×100 mm; CH₃CN—H₂O-5 mM NH₄OAc) and then by flashchromatography (SiO₂/hexane-ethyl acetate, 1:1) to provide the titlecompound (0.128 g, 17%) as an orange oil. ¹HNMR (400 MHz, CDCl₃) δ 8.90(d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.77 (ddd,J=8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J=8.3, 6.8, 1.5 Hz, 1H), 4.35 (s,1H), 4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, J=7.0 Hz, 3H). LCMS: Anal.Calcd. for C₁₅H₁₈N₂O₂: 258. found: 259 (M+H)⁺.

Step 2; (R,S) 2-(Quinolin-3-yl)-2-(N,N-dimethylamino)acetic acid: Amixture of (R,S)-ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)acetate(0.122 g, 0.472 mmol) and 6M HCl (3 mL) was heated at 100° C. for 12hours. The solvent was removed in vacuo to provide the dihydrochlorideof the title compound (0.169 g, >100%) as a light yellow foam. Theunpurified material was used in subsequent steps without furtherpurification. LCMS: Anal. Calcd. for C₁₃H₁₄N₂O₂: 230. found: 231 (M+H)⁺.

Step 1; (R)—((S)-1-phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate and (S)—((S)-1-phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate: To a mixture of(RS)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid (2.60 g, 13.19mmol), DMAP (0.209 g, 1.71 mmol) and (S)-1-phenylethanol (2.09 g, 17.15mmol) in CH₂Cl₂ (40 mL) was added EDCI (3.29 g, 17.15 mmol) and themixture was allowed to stir at room temperature for 12 hours. Thesolvent was then removed in vacuo and the residue partitioned with ethylacetate-H₂O. The layers were separated, the aqueous layer wasback-extracted with ethyl acetate (2×) and the combined organic phaseswere washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by silica gel chromatography(Biotage/0-50% diethyl ether-hexane). The resulting pure diastereomericmixture was then separated by reverse-phase preparative HPLC(Primesphere C-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give first(S)-1-phenethyl (R)-2-(dimethylamino)-2-(2-fluorophenyl)acetate (0.501g, 13%) and then (S)-1-phenethyl(S)-2-(dimethylamino)-2-(2-fluorophenyl)-acetate (0.727 g. 18%), both astheir TFA salts. (S,R)-isomer: ¹HNMR (400 MHz, CD₃OD) δ 7.65-7.70 (m,1H), 7.55-7.60 (ddd, J=9.4, 8.1, 1.5 Hz, 1H), 7.36-7.41 (m, 2H),7.28-7.34 (m, 5H), 6.04 (q, J=6.5 Hz, 1H), 5.60 (s, 1H), 2.84 (s, 6H),1.43 (d, J=6.5 Hz, 3H). LCMS: Anal. Calcd. for C₁₈H₂₀FNO₂: 301. found:302 (M+H)⁺; (S,S)-isomer: ¹HNMR (400 MHz, CD₃OD) δ 7.58-7.63 (m, 1H),7.18-7.31 (m, 6H), 7.00 (dd, J=8.5, 1.5 Hz, 2H), 6.02 (q, J=6.5 Hz, 1H),5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, J=6.5 Hz, 3H). LCMS: Anal. Calcd.for C₁₈H₂₀FNO₂: 301. found: 302 (M+H)⁺.

Step 2; (R)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid: A mixtureof (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetateTFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)₂/C (0.125 g) in ethanol (30mL) was hydrogenated at room temperature and atmospheric pressure (H₂balloon) for 4 hours. The solution was then purged with Ar, filteredthrough diatomaceous earth (Celite®), and concentrated in vacuo. Thisgave the title compound as a colorless solid (0.503 g, 98%). ¹HNMR (400MHz, CD₃OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86(s, 6H). LCMS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197. found: 198 (M+H)⁺.

The S-isomer could be obtained from (S)—((S)-1-phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt in similar fashion.

A mixture of (R)-(2-chlorophenyl)glycine (0.300 g, 1.62 mmol),formaldehyde (35% aqueous solution, 0.80 mL, 3.23 mmol) and 20%Pd(OH)₂/C (0.050 g) was hydrogenated at room temperature and atmosphericpressure (H₂ balloon) for 4 hours. The solution was then purged with Ar,filtered through diatomaceous earth (Celite®) and concentrated in vacuo.The residue was purified by reverse-phase preparative HPLC (PrimesphereC-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give the TFA salt of the titlecompound (R)-2-(dimethylamino)-2-(2-chlorophenyl)acetic acid as acolorless oil (0.290 g, 55%). ¹H NMR (400 MHz, CD₃OD) δ 7.59-7.65 (m,2H), 7.45-7.53 (m, 2H), 5.40 (s, 1H), 2.87 (s, 6H). LCMS: Anal. Calcd.for C₁₀H₁₂ClNO₂: 213, 215. found: 214, 216 (M+H)⁺.

To an ice-cold solution of (R)-(2-chlorophenyl)glycine (1.00 g, 5.38mmol) and NaOH (0.862 g, 21.6 mmol) in H₂O (5.5 mL) was added methylchloroformate (1.00 mL, 13.5 mmol) dropwise. The mixture was allowed tostir at 0° C. for 1 hour and then it was acidified by the addition ofconc. HCl (2.5 mL). The mixture was extracted with ethyl acetate (2×)and the combined organic phase was washed (H₂O, brine), dried (Na₂SO₄),filtered, and concentrated in vacuo to give the title compound(R)-2-(methoxycarbonylamino)-2-(2-chlorophenyl)acetic acid as ayellow-orange foam (1.31 g, 96%). ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.43(m, 2H), 7.29-7.31 (m, 2H), 5.69 (s, 1H), 3.65 (s, 3H). LCMS: Anal.Calcd. for C₁₀H₁₀ClNO₄: 243, 245. found: 244, 246 (M+H)⁺.

To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and thesolution was stirred at room temperature for 3 hours. The reactionmixture was then diluted with ethyl acetate and extracted with H₂O (2×).The aqueous phase was lyophilized and the residue was purified by silicagel chromatography (Biotage/0-10% methanol-CH₂Cl₂) to give the titlecompound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid(2.22 g, 87%). ¹HNMR (400 MHz, CD₃OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m,1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS:Anal. Calcd. for C₁₃H₁₇NO₃: 235. found: 236 (M+H)⁺.

The following examples were similarly prepared using the methoddescribed for Cap-41:

Cap-42

LCMS: Anal. Calcd. for C₁₄H₁₉NO₂: 233; found: 234(M+ H)⁺. Cap-43

LCMS: Anal. Calcd. for C₁₃H₁₇NO₂: 219; found: 220(M + H)⁺. Cap-44

LCMS: Anal. Calcd. for C₁₁H₁₅NO₂: 193; found: 194(M + H)⁺. Cap-45

LCMS: Anal. Calcd. for C₁₄H₂₀N₂O₂: 248; found: 249(M + H)⁺.

HMDS (1.85 mL, 8.77 mmol) was added to a suspension of(R)-2-amino-2-phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol)in CH₂Cl₂ (10 mL) and the mixture was stirred at room temperature for 30minutes. Methyl isocyanate (0.5 g, 8.77 mmol) was added in one portionstirring continued for 30 minutes. The reaction was quenched by additionof H₂O (5 mL) and the resulting precipitate was filtered, washed withH₂O and n-hexanes, and dried under vacuum.(R)-2-(3-methylureido)-2-phenylacetic acid (1.5 g; 82%) was recovered asa white solid and it was used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.54 (d, J=4.88 Hz, 3H) 5.17 (d, J=7.93 Hz, 1H) 5.95(q, J=4.48 Hz, 1H) 6.66 (d, J=7.93 Hz, 1H) 7.26-7.38 (m, 5H) 12.67 (s,1H). LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₃ 208.08 found 209.121 (M+H)⁺; HPLCPhenomenex C-18 3.0×46 mm, 0 to 100% B over 2 minutes, 1 minute holdtime, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol,0.1% TFA, RT=1.38 min, 90% homogeneity index.

The desired product was prepared according to the method described forCap-45. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.17 Hz, 3H)2.94-3.05 (m, 2H) 5.17 (d, J=7.93 Hz, 1H) 6.05 (t, J=5.19 Hz, 1H) 6.60(d, J=7.63 Hz, 1H) 7.26-7.38 (m, 5H) 12.68 (s, 1H). LCMS: Anal. Calcd.for C₁₁H₁₄N₂O₃ 222.10 found 209.121 (M+H)⁺.

HPLC XTERRA C-18 3.0×506 mm, 0 to 100% B over 2 minutes, 1 minutes holdtime, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water, 90% methanol,0.2% H₃PO₄, RT=0.87 min, 90% homogeneity index.

Step 1; (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate: To astirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was addeddimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wasdissolved in ethyl acetate. The organic layer was washed with H₂O, 1Naq. HCl and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetatewas obtained as a white solid (0.86 g; 75%) and used without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 2.82 (s, 6H)5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H). LCMS:Anal. Calcd. for C₁₅H₂₂N₂O₃ 278.16 found 279.23 (M+H)⁺; HPLC PhenomenexLUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time,A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1%TFA, RT=2.26 min, 97% homogeneity index.

Step 2; (R)-2-(3,3-dimethylureido)-2-phenylacetic acid: To a stirredsolution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86g, 3.10 mmol) in CH₂Cl₂ (250 mL) was added TFA (15 mL) dropwise and theresulting solution was stirred at rt for 3 h. The desired compound wasthen precipitated out of solution with a mixture of EtOAC:Hexanes(5:20), filtered off and dried under reduced pressure.(R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a whitesolid (0.59 g, 86%) and used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m,2H) 12.65 (s, 1H). LCMS: Anal. Calcd. for C₁₁H₁₄N₂O₃: 222.24. found:223.21 (M+H)⁺. HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water,90% methanol, 0.2% H₃PO₄, RT=0.75 min, 93% homogeneity index.

Step 1; (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate: To astirred solution of (R)-2-amino-2-phenylacetic acid hydrochloride (1.0g, 4.10 mmol) and Hunig's base (1.0 mL, 6.15 mmol) in DMF (15 mL) wasadded cyclopentyl isocyanate (0.46 mL, 4.10 mmol) dropwise and over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wastaken up in ethyl acetate. The organic layer was washed with H₂O andbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.(R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate was obtained asan opaque oil (1.32 g; 100%) and used without further purification. ¹HNMR (500 MHz, CD₃Cl-D) δ ppm 1.50-1.57 (m, 2H) 1.58-1.66 (m, 2H)1.87-1.97 (m, 2H) 3.89-3.98 (m, 1H) 5.37 (s, 1H) 7.26-7.38 (m, 5H).LCMS: Anal. Calcd. for C₁₈H₂₆N₂O₃ 318.19 found 319.21 (M+H)⁺; HPLCXTERRA C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time,A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1%TFA, RT=2.82 min, 96% homogeneity index.

Step 2; (R)-2-(3-cyclopentylureido)-2-phenylacetic acid: To a stirredsolution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31g, 4.10 mmol) in CH₂Cl₂ (25 mL) was added TFA (4 mL) and trietheylsilane(1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred atroom temperature for 6 hours. The volatile components were removed underreduced pressure and the crude product was recrystallized in ethylacetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylaceticacid as a white solid (0.69 g, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H)3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48(d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LCMS: Anal. Calcd.for C₁₄H₁₈N₂O₃: 262.31. found: 263.15 (M+H)⁺. HPLC XTERRA C-18 3.0×50mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=1.24min, 100% homogeneity index.

To a stirred solution of 2-(benzylamino)acetic acid (2.0 g, 12.1 mmol)in formic acid (91 mL) was added formaldehyde (6.94 mL, 93.2 mmol).After five hours at 70° C., the reaction mixture was concentrated underreduced pressure to 20 mL and a white solid precipitated. Followingfiltration, the mother liquors were collected and further concentratedunder reduced pressure providing the crude product. Purification byreverse-phase preparative HPLC (Xterra 30×100 mm, detection at 220 nm,flow rate 35 mL/min, 0 to 35% B over 8 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) provided the titlecompound 2-(benzyl(methyl)-amino)acetic acid as its TFA salt (723 mg,33%) as a colorless wax. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.75 (s, 3H)4.04 (s, 2H) 4.34 (s, 2H) 7.29-7.68 (m, 5H). LCMS: Anal. Calcd. for:C₁₀H₁₃NO₂ 179.22. Found: 180.20 (M+H)⁺.

To a stirred solution of 3-methyl-2-(methylamino)butanoic acid (0.50 g,3.81 mmol) in water (30 mL) was added K₂CO₃ (2.63 g, 19.1 mmol) andbenzyl chloride (1.32 g, 11.4 mmol). The reaction mixture was stirred atambient temperature for 18 hours. The reaction mixture was extractedwith ethyl acetate (30 mL×2) and the aqueous layer was concentratedunder reduced pressure providing the crude product which was purified byreverse-phase preparative HPLC (Xterra 30×100 mm, detection at 220 nm,flow rate 40 mL/min, 20 to 80% B over 6 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) to provide2-(benzyl(methyl)amino)-3-methylbutanoic acid, TFA salt (126 mg, 19%) asa colorless wax. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98 (d, 3H) 1.07 (d,3H) 2.33-2.48 (m, 1H) 2.54-2.78 (m, 3H) 3.69 (s, 1H) 4.24 (s, 2H)7.29-7.65 (m, 5H). LCMS: Anal. Calcd. for: C₁₃H₁₉NO₂ 221.30. Found:222.28 (M+H)⁺.

Na₂CO₃ (1.83 g, 17.2 mmol) was added to NaOH (33 mL of 1M/H₂O, 33 mmol)solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution wascooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) wasadded drop-wise over 15 min, the cooling bath was removed and thereaction mixture was stirred at ambient temperature for 3.25 hr. Thereaction mixture was washed with ether (50 mL, 3×), and the aqueousphase was cooled with ice-water bath and acidified with concentrated HClto a pH region of 1-2, and extracted with CH₂Cl₂ (50 mL, 3×). Theorganic phase was dried (MgSO₄), filtered, and concentrated in vacuo toafford Cap-51 as a white solid (6 g). ¹H NMR for the dominant rotamer(DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.54 (s, 1H), 7.33 (d, J=8.6, 1H), 3.84(dd, J=8.4, 6.0, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS:Anal. Calcd. for [M+H]⁺ C₇H₁₄NO₄: 176.0923. found 176.0922

Cap-52 was synthesized from L-alanine according to the proceduredescribed for the synthesis of Cap-51. For characterization purposes, aportion of the crude material was purified by a reverse phase HPLC(H₂O/MeOH/TFA) to afford Cap-52 as a colorless viscous oil. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.49 (br s, 1H), 7.43 (d, J=7.3, 0.88H),7.09 (app br s, 0.12H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3, 3H).

Cap-53 to −64 were prepared from appropriate starting materialsaccording to the procedure described for the synthesis of Cap-51, withnoted modifications if any.

Cap Structure Data Cap-53a: (R) Cap-53b: (S)

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.51(br s, 1 H), 7.4(d, J =7.9, 0.9 H), 7.06 (app s, 0.1 H), 3.86-3.82(m, 1 H), 3.53(s, 3 H),1.75-1.67(m, 1 H), 1.62-1.54(m, 1 H), 0.88(d, J = 7.3, 3 H). RT = 0.77minutes(Cond. 2); LC/MS: Anal. Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.06;found 184.07. HRMS Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.0586; found184.0592. Cap-54a: (R) Cap-54b: (S)

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.48(s, 1 H), 7.58(d, J = 7.6,0.9 H), 7.25 (app s, 0.1 H), 3.52(s, 3 H), 3.36-3.33(m, 1 H),1.10-1.01(m, 1 H), 0.54-0.49(m, 1 H), 0.46- 0.40(m, 1 H), 0.39-0.35(m, 1H), 0.31-0.21(m, 1 H). HRMS Calcd. for [M + H]⁺ C₇H₁₂NO₄: 174.0766;found 174.0771 Cap-55

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.62(s, 1 H), 7.42(d, J = 8.2,0.9 H), 7.07 (app s, 0.1 H), 5.80-5.72(m, 1 H), 5.10(d, J = 17.1, 1 H),5.04(d, J = 10.4, 1 H), 4.01-3.96 (m, 1 H), 3.53(s, 3 H), 2.47-2.42(m, 1H), 2.35- 2.29(m, 1 H). Cap-56

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.75(s, 1 H), 7.38(d, J = 8.3,0.9 H), 6.96 (app s, 0.1 H), 4.20-4.16(m, 1 H), 3.60-3.55(m, 2 H),3.54(s, 3 H), 3.24(s, 3 H). Cap-57

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.50(s, 1 H), 8.02(d, J = 7.7,0.08 H), 7.40 (d, J = 7.9, 0.76 H), 7.19(d, J = 8.2, 0.07 H), 7.07(d, J= 6.7, 0.09 H), 4.21-4.12(m, 0.08 H), 4.06-3.97(m, 0.07 H), 3.96-3.80(m,0.85 H), 3.53(s, 3 H), 1.69-1.51(m, 2 H), 1.39-1.26(m, 2 H), 0.85(t, J =7.4, 3 H). LC(Cond. 2): RT = 1.39 LC/MS: Anal. Calcd. for [M + H]⁺C₇H₁₄NO₄: 176.09; found 176.06. Cap-58

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.63(bs, 1 H), 7.35(s, 1 H),7.31(d, J = 8.2, 1 H), 6.92(s, 1 H), 4.33-4.29(m, 1 H), 3.54(s, 3 H),2.54(dd, J = 15.5, 5.4, 1 H), 2.43(dd, J = 15.6, 8.0, 1 H). RT = 0.16min (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₆H₁₁N₂O₅: 191.07; found191.14. Cap-59a: (R) Cap-59b: (S)

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.49(br s, 1 H), 7.40(d, J =7.3, 0.89 H), 7.04(br s, 0.11 H), 4.00-3.95(m, 3 H), 1.24(d, J = 7.3, 3H), 1.15(t, J = 7.2, 3 H). HRMS: Anal. Calcd. for [M + H]⁺ C₆H₁₂NO₄:162.0766; found 162.0771. Cap-60

The crude material was purified with a reverse phase HPLC(H₂O/MeOH/TFA)to afford a colorless viscous oil that crystallized to a white solidupon exposure to high vacuum. ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ12.38 (br s, 1 H), 7.74(s, 0.82 H), 7.48(s, 0.18 H), 3.54/3.51(two s, 3H), 1.30(m, 2 H), 0.98(m, 2 H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₀NO₄: 160.0610; found 160.0604. Cap-61

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.27(br s, 1 H), 7.40(br s, 1H), 3.50(s, 3 H), 1.32(s, 6 H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₂NO₄: 162.0766; found 162.0765. Cap-62

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.74(br s, 1 H), 4.21(d, J =10.3, 0.6 H), 4.05(d, J = 10.0, 0.4 H), 3.62/3.60(two singlets, 3 H),3.0(s, 3 H), 2.14-2.05(m, 1 H), 0.95(d, J = 6.3, 3 H), 0.81(d, J = 6.6,3 H). LC/MS: Anal. Calcd. for [M − H]⁻ C₈H₁₄NO₄: 188.09; found 188.05.Cap-63

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz):12.21(br s, 1 H), 7.42(br s, 1 H), 3.50(s, 3 H), 2.02-1.85(m, 4 H),1.66-1.58(m, 4 H). LC/MS: Anal. Calcd. for [M + H]⁺ C₈H₁₄NO₄: 188.09;found 188.19. Cap-64

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz):12.35(br s, 1 H), 7.77(s, 0.82 H), 7.56/7.52(overlapping br s, 0.18 H),3.50(s, 3 H), 2.47-2.40(m, 2 H), 2.14-2.07(m, 2 H), 1.93-1.82(m, 2 H).

Methyl chloroformate (0.65 mL, 8.39 mmol) was added dropwise over 5 minto a cooled (ice-water) mixture of Na₂CO₃ (0.449 g, 4.23 mmol), NaOH(8.2 mL of 1M/H₂O, 8.2 mmol) and(s)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoic acid (1.04 g,7.81 mmol). The reaction mixture was stirred for 45 min, and then thecooling bath was removed and stirring was continued for an additional3.75 hr. The reaction mixture was washed with CH₂Cl₂, and the aqueousphase was cooled with ice-water bath and acidified with concentrated HClto a pH region of 1-2. The volatile component was removed in vacuo andthe residue was taken up in a 2:1 mixture of MeOH/CH₂Cl₂ (15 mL) andfiltered, and the filterate was rotervaped to afford Cap-65 as a whitesemi-viscous foam (1.236 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ6.94 (d, J=8.5, 0.9H), 6.53 (br s, 0.1H), 3.89 (d, J=8.8, 1H), 2.94 (s,3H), 1.15 (s, 3H), 1.13 (s, 3H).

Cap-66 and -67 were prepared from appropriate commercially availablestarting materials by employing the procedure described for thesynthesis of Cap-65.

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.58 (br s, 1H), 7.07 (d,J=8.3, 0.13H), 6.81 (d, J=8.8, 0.67H), 4.10-4.02 (m, 1.15H), 3.91 (dd,J=9.1, 3.5, 0.85H), 3.56 (s, 3H), 1.09 (d, J=6.2, 3H). [Note: only thedominant signals of NH were noted].

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, J=8.4,0.75H), 7.12 (br d, J=0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m,2H), 3.54 (s, 3H), 1.08 (d, J=6.3, 3H). [Note: only the dominant signalsof NH were noted]

Methyl chloroformate (0.38 ml, 4.9 mmol) was added drop-wise to amixture of 1N NaOH (aq) (9.0 ml, 9.0 mmol), 1M NaHCO₃ (aq) (9.0 ml, 9.0mol), L-aspartic acid β-benzyl ester (1.0 g, 4.5 mmol) and Dioxane (9ml). The reaction mixture was stirred at ambient conditions for 3 hr,and then washed with Ethyl acetate (50 ml, 3×). The aqueous layer wasacidified with 12N HCl to a pH˜1-2, and extracted with ethyl acetate(3×50 ml). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to afford Cap-68 as alight yellow oil (1.37 g; mass is above theoretical yield, and theproduct was used without further purification). ¹H NMR (DMSO-d₆, δ=2.5ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d, J=8.5, 1H), 7.40-7.32 (m,5H), 5.13 (d, J=12.8, 1H), 5.10 (d, J=12.9, 1H), 4.42-4.38 (m, 1H), 3.55(s, 3H), 2.87 (dd, J=16.2, 5.5, 1H), 2.71 (dd, J=16.2, 8.3, 1H). LC(Cond. 2): RT=1.90 min; LC/MS: Anal. Calcd. For [M+H]⁺ C₁₃H₁₆NO₆:282.10. found 282.12.

NaCNBH₃ (2.416 g, 36.5 mmol) was added in batches to a chilled (˜15° C.)water (17 mL)/MeOH (10 mL) solution of alanine (1.338 g, 15.0 mmol). Afew minutes later acetaldehyde (4.0 mL, 71.3 mmol) was added drop-wiseover 4 min, the cooling bath was removed, and the reaction mixture wasstirred at ambient condition for 6 hr. An additional acetaldehyde (4.0mL) was added and the reaction was stirred for 2 hr. Concentrated HClwas added slowly to the reaction mixture until the pH reached ˜1.5, andthe resulting mixture was heated for 1 hr at 40° C. Most of the volatilecomponent was removed in vacuo and the residue was purified with aDowex® 50WX8-100 ion-exchange resin (column was washed with water, andthe compound was eluted with dilute NH₄OH, prepared by mixing 18 ml ofNH₄OH and 282 ml of water) to afford Cap-69 (2.0 g) as an off-white softhygroscopic solid. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 3.44 (q,J=7.1, 1H), 2.99-2.90 (m, 2H), 2.89-2.80 (m, 2H), 1.23 (d, J=7.1, 3H),1.13 (t, J=7.3, 6H).

Cap-70 to −74 were prepared according to the procedure described for thesynthesis of Cap-69 by employing appropriate starting materials.

Cap-70a: (R) Cap-70b: (S)

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 3.42(q, J = 7.1, 1 H),2.68-2.60(m, 4 H), 1.53-1.44(m, 4 H), 1.19(d, J = 7.3, 3 H), 0.85 (t, J= 7.5, 6 H). LC/MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂: 174.15; found174.13. Cap-71a: (R) Cap-71b: (S)

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 3.18-3.14(m, 1 H), 2.84-2.77(m,2 H), 2.76- 2.68(m, 2 H), 1.69-1.54(m, 2 H), 1.05(t, J = 7.2, 6 H),0.91(t, J = 7.3, 3 H). LC/MS: Anal. Calcd. for [M + H]⁺ C₈H₁₈NO₂:160.13; found 160.06. Cap-72

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 2.77-2.66(m, 3 H), 2.39-2.31(m,2 H), 1.94- 1.85(m, 1 H), 0.98(t, J = 7.1, 6 H), 0.91(d, J = 6.5, 3 H),0.85(d, J = 6.5, 3 H). LC/MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂:174.15; found 174.15. Cap-73

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 9.5(br s, 1 H), 3.77(dd, J =1.8, 4.1, 1 H), 3.69-3.61(m, 2 H), 3.26(s, 3 H), 2.99-2.88(m, 4 H),1.13(t, J = 7.2, 6 H). Cap-74

¹H NMR(DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 7.54(s, 1 H), 6.89(s, 1 H),3.81(t, J = 6.6, k, 1 H), 2.82-2.71(m, 4 H), 2.63(dd, J = 15.6, 7.0, 1H), 2.36(dd, J = 15.4, 6.3, 1 H), 1.09(t, J = 7.2, 6 H). RT = 0.125minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₈H₁₇N₂O₃: 189.12;found 189.13. Cap-74x

LC/MS: Anal. Calcd. for [M + H]⁺ C₁₀H₂₂NO₂: 188.17; found 188.21

NaBH₃CN (1.6 g, 25.5 mmol) was added to a cooled (ice/water bath) water(25 ml)/methanol (15 ml) solution of H-D-Ser-OBzl HCl (2.0 g, 8.6 mmol).Acetaldehyde (1.5 ml, 12.5 mmol) was added drop-wise over 5 min, thecooling bath was removed, and the reaction mixture was stirred atambient condition for 2 hr. The reaction was carefully quenched with 12NHCl and concentrated in vacuo. The residue was dissolved in water andpurified with a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof (R)-benzyl 2-(diethylamino)-3-hydroxypropanoate as a colorlessviscous oil (1.9 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): δ 9.73 (br s,1H), 7.52-7.36 (m, 5H), 5.32 (d, J=12.2, 1H), 5.27 (d, J=12.5, 1H),4.54-4.32 (m, 1H), 4.05-3.97 (m, 2H), 3.43-3.21 (m, 4H), 1.23 (t, J=7.2,6H). LC/MS (Cond. 2): RT=1.38 min; LC/MS: Anal. Calcd. for [M+H]⁺C₁₄H₂₂NO₃: 252.16. found 252.19.

Cap-75

NaH (0.0727 g, 1.82 mmol, 60%) was added to a cooled (ice-water) THF(3.0 mL) solution of the TFA salt (R)-benzyl2-(diethylamino)-3-hydroxypropanoate (0.3019 g, 0.8264 mmol) preparedabove, and the mixture was stirred for 15 min. Methyl iodide (56 μL,0.90 mmol) was added and stirring was continued for 18 hr while allowingthe bath to thaw to ambient condition. The reaction was quenched withwater and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, andwashed with methanol followed by compound elution with 2N NH₃/Methanol.Removal of the volatile component in vacuo afforded Cap-75, contaminatedwith (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellowsemi-solid (100 mg). The product was used as is without furtherpurification.

NaCNBH₃ (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.)water/MeOH (12 mL each) solution of(S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was addeddrop-wise over 2 min, the cooling bath was removed, and the reactionmixture was stirred at ambient condition for 3.5 hr. An additionalacetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirredfor 20.5 hr. Most of the MeOH component was removed in vacuo, and theremaining mixture was treated with concentrated HCl until its pH reached˜1.0 and then heated for 2 hr at 40° C. The volatile component wasremoved in vacuo, and the residue was treated with 4 M HCl/dioxane (20mL) and stirred at ambient condition for 7.5 hr. The volatile componentwas removed in vacuo and the residue was purified with Dowex ® 50WX8-100ion-exchange resin (column was washed with water and the compound waseluted with dilute NH₄OH, prepared from 18 ml of NH₄OH and 282 ml ofwater) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acidas an off-white solid (1.73 g).

Methyl chloroformate (0.36 mL, 4.65 mmol) was added drop-wise over 11min to a cooled (ice-water) mixture of Na₂CO₃ (0.243 g, 2.29 mmol), NaOH(4.6 mL of 1M/H₂O, 4.6 mmol) and the above product (802.4 mg). Thereaction mixture was stirred for 55 min, and then the cooling bath wasremoved and stirring was continued for an additional 5.25 hr. Thereaction mixture was diluted with equal volume of water and washed withCH₂Cl₂ (30 mL, 2×), and the aqueous phase was cooled with ice-water bathand acidified with concentrated HCl to a pH region of 2. The volatilecomponent was then removed in vacuo and the crude material wasfree-based with MCX resin (6.0 g; column was washed with water, andsample was eluted with 2.0 M NH₃/MeOH) to afford impure Cap-76 as anoff-white solid (704 mg). ¹H NMR (MeOH-d₄, δ=3.29 ppm, 400 MHz): δ 3.99(dd, J=7.5, 4.7, 1H), 3.62 (s, 3H), 3.25-3.06 (m, 6H), 2.18-2.09 (m,1H), 2.04-1.96 (m, 1H), 1.28 (t, J=7.3, 6H). LC/MS: Anal. Calcd. for[M+H]⁺ C₁₀H₂₁N₂O₄: 233.15. found 233.24.

The synthesis of Cap-77 was conducted according to the proceduredescribed for Cap-7 by using 7-azabicyclo[2.2.1]heptane for the SN₂displacement step, and by effecting the enantiomeric separation of theintermediate benzyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylacetateusing the following condition: the intermediate (303.7 mg) was dissolvedin ethanol, and the resulting solution was injected on a chiral HPLCcolumn (Chiracel AD-H column, 30×250 mm, 5 um) eluting with 90% CO₂-10%EtOH at 70 mL/min, and a temperature of 35° C. to provide 124.5 mg ofenantiomer-1 and 133.8 mg of enantiomer-2. These benzyl esters werehydrogenolysed according to the preparation of Cap-7 to provide Cap-77:¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H),4.16 (s, 1H), 3.54 (app br s, 2H), 2.08-1.88 (m, 4H), 1.57-1.46 (m, 4H).LC (Cond. 1): RT=0.67 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₄H₁₈BrNO₂:232.13. found 232.18. HRMS: Anal. Calcd. for [M+H]⁺ C₁₄H₁₈BrNO₂:232.1338. found 232.1340.

NaCNBH₃ (0.5828 g, 9.27 mmol) was added to a mixture of the HCl salt of(R)-2-(ethylamino)-2-phenylacetic acid (an intermediate in the synthesisof Cap-3; 0.9923 mg, 4.60 mmol) and(1-ethoxycyclopropoxy)trimethylsilane (1.640 g, 9.40 mmol) in MeOH (10mL), and the semi-heterogeneous mixture was heated at 50° C. with an oilbath for 20 hr. More (1-ethoxycyclopropoxy)trimethylsilane (150 mg, 0.86mmol) and NaCNBH₃ (52 mg, 0.827 mmol) were added and the reactionmixture was heated for an additional 3.5 hr. It was then allowed to coolto ambient temperature and acidified to a ˜pH region of 2 withconcentrated HCl, and the mixture was filtered and the filtrate wasrotervaped. The resulting crude material was taken up in i-PrOH (6 mL)and heated to effect dissolution, and the non-dissolved part wasfiltered off and the filtrate concentrated in vacuo. About ⅓ of theresultant crude material was purified with a reverse phase HPLC(H₂O/MeOH/TFA) to afford the TFA salt of Cap-78 as a colorless viscousoil (353 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz; after D₂O exchange):δ 7.56-7.49 (m, 5H), 5.35 (S, 1H), 3.35 (m, 1H), 3.06 (app br s, 1H),2.66 (m, 1H), 1.26 (t, J=7.3, 3H), 0.92 (m, 1H), 0.83-0.44 (m, 3H). LC(Cond. 1): RT=0.64 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂:220.13. found 220.21. HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂: 220.1338.found 220.1343.

Ozone was bubbled through a cooled (−78° C.) CH₂Cl₂ (5.0 mL) solutionCap-55 (369 mg, 2.13 mmol) for about 50 min until the reaction mixtureattained a tint of blue color. Me₂S (10 pipet drops) was added, and thereaction mixture was stirred for 35 min. The −78° C. bath was replacedwith a −10° C. bath and stirring continued for an additional 30 min, andthen the volatile component was removed in vacuo to afford a colorlessviscous oil.

NaBH₃CN (149 mg, 2.25 mmol) was added to a MeOH (5.0 mL) solution of theabove crude material and morpholine (500 μL, 5.72 mmol) and the mixturewas stirred at ambient condition for 4 hr. It was cooled to ice-watertemperature and treated with concentrated HCl to bring its pH to ˜2.0,and then stirred for 2.5 hr. The volatile component was removed invacuo, and the residue was purified with a combination of MCX resin(MeOH wash; 2.0 N NH₃/MeOH elution) and a reverse phase HPLC(H₂O/MeOH/TFA) to afford Cap-79 containing unknown amount of morpholine.

In order to consume the morpholine contaminant, the above material wasdissolved in CH₂Cl₂ (1.5 mL) and treated with Et₃N (0.27 mL, 1.94 mmol)followed by acetic anhydride (0.10 mL, 1.06 mmol) and stirred at ambientcondition for 18 hr. THF (1.0 mL) and H₂O (0.5 mL) were added andstirring continued for 1.5 hr. The volatile component was removed invacuo, and the resultant residue was passed through MCX resin (MeOHwash; 2.0 N NH₃/MeOH elution) to afford impure Cap-79 as a brown viscousoil, which was used for the next step without further purification.

SOCl₂ (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled(ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid(10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removedand the reaction mixture was stirred at ambient condition for 29 hr.Most of the volatile component was removed in vacuo and the residue wascarefully partitioned between EtOAc (150 mL) and saturated NaHCO₃solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), andthe combined organic phase was dried (MgSO₄), filtered, and concentratedin vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorlessoil (9.706 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m,5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd,J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond.1): RT=0.90 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₄: 238.11. found238.22.

Pb(NO₃)₂ (6.06 g, 18.3 mmol) was added over 1 min to a CH₂Cl₂ (80 mL)solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol),9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et₃N (3.0 mL, 21.5mmol), and the heterogeneous mixture was stirred at ambient conditionfor 48 hr. The mixture was filtered and the filtrate was treated withMgSO₄ and filtered again, and the final filtrate was concentrated. Theresulting crude material was submitted to a Biotage purification (350 gsilica gel, CH₂Cl₂ elution) to afford (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorlessoil (7.93 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H),7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d,J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partiallyoverlapped with solvent). LC (Cond. 1): RT=2.16 min; LC/MS: Anal. Calcd.for [M+H]⁺ C₃₁H₂₈NO₄: 478.20. found 478.19.

LiHMDS (9.2 mL of 1.0 M/THF, 9.2 mmol) was added drop-wise over 10 minto a cooled (−78° C.) THF (50 mL) solution of (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.907 g, 8.18 mmol) andstirred for 1 hr. MeI (0.57 mL, 9.2 mmol) was added drop-wise over 8 minto the mixture, and stirring was continued for 16.5 hr while allowingthe cooling bath to thaw to room temperature. After quenching withsaturated NH₄Cl solution (5 mL), most of the organic component wasremoved in vacuo and the residue was partitioned between CH₂Cl₂ (100 mL)and water (40 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo, and the resulting crude material was purifiedwith a Biotage (350 g silica gel; 25% EtOAc/hexanes) to afford 3.65 g ofa 2S/3S and 2S/3R diastereomeric mixtures of 1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate in ˜1.0:0.65 ratio(¹H NMR). The stereochemistry of the dominant isomer was not determinedat this juncture, and the mixture was submitted to the next step withoutseparation. Partial ¹H NMR data (DMSO-d₆, δ=2.5 ppm, 400 MHz): majordiastereomer, δ 4.39 (d, J=12.3, 1H of CH₂), 3.33 (s, 3H, overlappedwith H₂O signal), 3.50 (d, J=10.9, NH), 1.13 (d, J=7.1, 3H); minordiastereomer, δ 4.27 (d, J=12.3, 1H of CH₂), 3.76 (d, J=10.9, NH), 3.64(s, 3H), 0.77 (d, J=7.0, 3H). LC (Cond. 1): RT=2.19 min; LC/MS: Anal.Calcd. for [M+H]⁺ C₃₂H₃₀NO₄: 492.22. found 492.15.

Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol)was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL)solution of (2S)-1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol)prepared above, and stirred at −78° C. for 20 hr. The reaction mixturewas removed from the cooling bath and rapidly poured into ˜1M H₃PO₄/H₂O(250 mL) with stirring, and the mixture was extracted with ether (100mL, 2×). The combined organic phase was washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. A silica gel mesh of thecrude material was prepared and submitted to chromatography (25%EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with benzyl alcohol, as a colorless viscous oil and(2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containingthe (2S,3R) stereoisomer as an impurity. The later sample wasresubmitted to the same column chromatography purification conditions toafford 750 mg of purified material as a white foam. [Note: the (2S,3S)isomer elutes before the (2S,3R) isomer under the above condition].(2S,3S) isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H),7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21(app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H),˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d,J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC/MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45. found 464.22. (2S,3R) isomer: ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1,1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H),3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8,3H). LC (Cond. 1): RT=1.92 min; LC/MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45. found 464.52.

The relative stereochemical assignments of the DIBAL-reduction productswere made based on NOE studies conducted on lactone derivatives preparedfrom each isomer by employing the following protocol: LiHMDS (50 μL of1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL)solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg,0.135 mmol), and the reaction mixture was stirred at similar temperaturefor ˜2 hr. The volatile component was removed in vacuo and the residuewas partitioned between CH₂Cl₂ (30 mL), water (20 mL) and saturatedaqueous NH₄Cl solution (1 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo, and the resulting crude materialwas submitted to a Biotage purification (40 g silica gel; 10-15%EtOAc/hexanes) to afford(3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-oneas a colorless film of solid (28.1 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to(3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one.(3S,4S)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.83 (d,J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8,NH), 3.45 (app t, J=9.2, 1H), ˜2.47 (m, 1H, partially overlapped withsolvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1):RT=1.98 min; LC/MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15. found378.42. (3S,4R)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz),7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd,J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, J=3.0, NH), 2.92 (dd,J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03min; LC/MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15. found 378.49.

TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol)were added to a CH₂Cl₂ (3 ml) solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg,0.258 mmol), and the mixture was stirred at ambient condition for 14.25hr. The reaction mixture was then diluted with CH₂Cl₂ (30 mL) and washedwith water (15 mL), and the organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. The resultant crude material was purifiedwith a Biotage (40 g silica gel; 5% EtOAc/hexanes) to afford(2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with TBDMS based impurities, as a colorless viscous oil(124.4 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate.(2S,3S)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.82(d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16H), 4.70 (d,J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1,5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s,3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4min): RT=3.26 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₇H₄₄NO₃Si: 578.31.found 578.40. (2S,3R)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H),4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H),3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3,1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H),−0.08 (s, 3H).

A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate(836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and themixture was stirred at room temperature for ˜21 hr, where the balloonwas recharged with H₂ as necessary. The reaction mixture was dilutedwith CH₂Cl₂ and filtered through a pad of diatomaceous earth(Celite-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH(1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase wasconcentrated, and a silica gel mesh was prepared from the resultingcrude material and submitted to a flash chromatography (8:2:1 mixture ofEtOAc/i-PrOH/H₂O) to afford(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid asa white fluffy solid (325 mg). (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoatewas similarly elaborated to(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid.(2S,3S)-amino acid isomer: ¹H NMR (Methanol-d₄, δ=3.29 ppm, 400 MHz),3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0,1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H).LC/MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si: 248.17. found 248.44.(2S,3R)-amino acid isomer: ¹H NMR (Methanol-d₄, δ=3.29 ppm, 400 MHz),3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3,3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si:248.17. found 248.44.

Water (1 mL) and NaOH (0.18 mL of 1.0 M/H₂O, 0.18 mmol) were added to amixture of(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid(41.9 mg, 0.169 mmol) and Na₂CO₃ (11.9 mg, 0.112 mmol), and sonicatedfor about 1 min to effect dissolution of reactants. The mixture was thencooled with an ice-water bath, methyl chloroformate (0.02 mL, 0.259mmol) was added over 30 s, and vigorous stirring was continued atsimilar temperature for 40 min and then at ambient temperature for 2.7hr. The reaction mixture was diluted with water (5 mL), cooled withice-water bath and treated drop-wise with 1.0 N HCl aqueous solution(˜0.23 mL). The mixture was further diluted with water (10 mL) andextracted with CH₂Cl₂ (15 mL, 2×). The combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo to afford Cap-80a as anoff-white solid.(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid wassimilarly elaborated to Cap-80b. Cap-80a: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 12.57 (br s, 1H), 7.64 (d, J=8.3, 0.3H), 7.19 (d, J=8.8,0.7H), 4.44 (dd, J=8.1, 4.6, 0.3H), 4.23 (dd, J=8.7, 4.4, 0.7H),3.56/3.53 (two singlets, 3H), 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85(s, 9H), ˜0.84 (d, 0.9H, overlapped with t-Bu signal), 0.79 (d, J=7,2.1H), 0.02/0.01/0.00 (three overlapping singlets, 6H). LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16. found 328.46. Cap-80b: ¹H NMR(CDCl₃, δ=7.24 ppm, 400 MHz), 6.00 (br d, J=6.8, 1H), 4.36 (dd, J=7.1,3.1, 1H), 3.87 (dd, J=10.5, 3.0, 1H), 3.67 (s, 3H), 3.58 (dd, J=10.6,4.8, 1H), 2.35 (m, 1H), 1.03 (d, J=7.1, 3H), 0.90 (s, 9H), 0.08 (s, 6H).LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16. found 328.53. Thecrude products were utilized without further purification.

Prepared according to the protocol described by Falb et al. SyntheticCommunications 1993, 23, 2839.

Cap-82 to Cap-85

Cap-82 to Cap-85 were synthesized from appropriate starting materialsaccording to the procedure described for Cap-51. The samples exhibitedsimilar spectral profiles as that of their enantiomers (i.e., Cap-4,Cap-13, Cap-51 and Cap-52, respectively)

To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g,22.55 mmol) in H₂O (15 mL) was added ClCO₂Me (1.74 mL, 22.55 mmol)dropwise at 0° C. The mixture was allowed to stir for 12 h and acidifiedto pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and(2×250 mL) and 10% MeOH in CH₂Cl₂ (250 mL) and the combined organicphases were concentrated under in vacuo to afford a colorless oil (4.18g, 97%) which was of sufficient purity for use in subsequent steps.¹HNMR (400 MHz, CDCl₃) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H),1.17 (d, J=7.7 Hz, 3H). LCMS: Anal. Calcd. for C₇H₁₃NO₅: 191. found: 190(M−H)⁻.

To a mixture of L-homoserine (2.0 g, 9.79 mmol), Na₂CO₃ (2.08 g, 19.59mmol) in H₂O (15 mL) was added ClCO₂Me (0.76 mL, 9.79 mmol) dropwise at0° C. The mixture was allowed to stir for 48 h and acidified to pH 1using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL)and the combined organic phases were concentrated under in vacuo toafford a colorless solid (0.719 g, 28%) which was of sufficient purityfor use in subsequent steps. ¹HNMR (400 MHz, CDCl₃) δ 4.23 (dd, J=4.5,9.1 Hz, 1H), 3.66 (s, 3H), 3.43-3.49 (m, 2H), 2.08-2.14 (m, 1H),1.82-1.89 (m, 1H). LCMS: Anal. Calcd. for C₇H₁₃NO₅: 191. found: 192(M+H)⁺.

A mixture of L-valine (1.0 g, 8.54 mmol), 3-bromopyridine (1.8 mL, 18.7mmol), K₂CO₃ (2.45 g, 17.7 mmol) and CuI (169 mg, 0.887 mmol) in DMSO(10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooledto rt, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2). Theorganic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophilized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹HNMR (400 MHz,DMSO-d₆) δ 8.00 (s, br, 1H), 7.68-7.71 (m, 1H), 7.01 (s, br, 1H), 6.88(d, J=7.5 Hz, 1H), 5.75 (s, br, 1H), 3.54 (s, 1H), 2.04-2.06 (m, 1H),0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. forC₁₀H₁₄N₂O₂: 194. found: 195 (M+H)⁺.

A mixture of L-valine (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g,17.0 mmol), K₂CO₃ (2.40 g, 17.4 mmol) and CuI (179 mg, 0.94 mmol) inDMSO (10 mL) was heated at 100° C. for 12 h. The reaction mixture wascooled to RT, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2).The organic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophilized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹HNMR (400 MHz,CD₃OD) showed the mixture to contain valine and the purity could not beestimated. The material was used as is in subsequent reactions. LCMS:Anal. Calcd. for C₉H₁₃N₃O₂: 195. found: 196 (M+H)⁺.

Cap-90 was prepared according to the method described for thepreparation of Cap-1. The crude material was used as is in subsequentsteps. LCMS: Anal. Calcd. for C₁₁H₁₅NO₂: 193. found: 192 (M−H)⁻.

The following caps were prepared according to the method of example 51:

Cap Structure LCMS Cap-91

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-92

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-93

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-94

LCMS: Anal. Calcd. for C₈H₁₁N₃O₄: 213; found: 214 (M + H)⁺. Cap-95

LCMS: Anal. Calcd. for C₁₃H₁₇NO₄: 251; found: 250 (M − H)⁻. Cap-96

LCMS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 236 (M − H)⁻. Cap-97

LCMS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 200 (M − H)⁻. Cap-98

LCMS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 202 (M + H)⁺. Cap-99

¹HNMR(400 MHz, CD₃OD) δ 3.88-3.94(m, 1 H), 3.60, 3.61(s, 3 H), 2.80(m, 1H), 2.20(m, 1 H), 1.82-1.94(m, 3 H), 1.45-1.71(m, 2 H). Cap-99a

¹HNMR(400 MHz, CD₃OD) δ 3.88-3.94(m, 1 H), 3.60, 3.61(s, 3 H), 2.80(m, 1H), 2.20(m, 1 H), 1.82-1.94(m, 3 H), 1.45-1.71(m, 2 H). Cap-100

LCMS: Anal. Calcd. for C₁₂H₁₄NO₄F: 255; found: 256(M + H)⁺. Cap-101

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-102

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻ Cap-103

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-104

¹HNMR(400 MHz, CD₃OD) δ 3.60(s, 3 H), 3.50-3.53 (m, 1 H), 2.66-2.69 and2.44- 2.49(m, 1 H), 1.91-2.01 (m, 2 H), 1.62-1.74(m, 4 H), 1.51-1.62(m,2 H). Cap-105

¹HNMR(400 MHz, CD₃OD) δ 3.60(s, 3 H), 3.33-3.35 (m, 1 H, partiallyobscured by solvent), 2.37-2.41 and 2.16-2.23(m, 1 H), 1.94- 2.01(m, 4H), 1.43-1.53(m, 2 H), 1.17-1.29(m, 2 H). Cap-106

¹HNMR(400 MHz, CD₃OD) δ 3.16(q, J = 7.3 Hz, 4 H), 2.38-2.41(m, 1 H),2.28- 2.31(m, 2 H), 1.79-1.89(m, 2 H), 1.74(app, ddd J = 3.5, 12.5, 15.9Hz, 2 H), 1.46(app dt J = 4.0, 12.9 Hz, 2 H), 1.26 (t, J = 7.3 Hz, 6 H).Cap-107

LCMS: Anal. Calcd. for C₈H₁₀N₂O₄S: 230; found: 231(M + H)⁺. Cap-108

LCMS: Anal. Calcd. for C₁₅H₁₇N₃O₄: 303; found: 304 (M + H)⁺. Cap-109

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-110

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-111

LCMS: Anal. Calcd. for C₁₂H₁₆NO₈P: 333; found: 334(M + H)⁺. Cap-112

LCMS: Anal. Calcd. for C₁₃H₁₄N₂O₄: 262; found: 263 (M + H)⁺. Cap-113

LCMS: Anal. Calcd. for C₁₈H₁₉NO₅: 329; found: 330 (M + H)⁺. Cap-114

¹HNMR(400 MHz, CDCl₃) δ 4.82-4.84(m, 1 H), 4.00- 4.05(m, 2 H), 3.77(s, 3H), 2.56(s, br, 2 H) Cap-115

¹HNMR(400 MHz, CDCl₃) δ 5.13(s, br, 1 H), 4.13(s, br, 1 H), 3.69(s, 3H), 2.61(d, J = 5.0 Hz, 2 H), 1.28(d, J = 9.1 Hz, 3 H). Cap-116

¹HNMR(400 MHz, CDCl₃) δ 5.10(d, J = 8.6 Hz, 1 H), 3.74-3.83(m, 1 H),3.69(s, 3 H), 2.54-2.61(m, 2 H), 1.88(sept, J = 7.0 Hz, 1 H), 0.95(d, J= 7.0 Hz, 6 H).

Cap-117 to Cap-123

For the preparation of caps Cap-117 to Cap-123 the Boc amino acids werecommercially available and were deprotected by treatment with 25% TFA inCH₂Cl₂. After complete reaction as judged by LCMS the solvents wereremoved in vacuo and the corresponding TFA salt of the amino acid wascarbamoylated with methyl chloroformate according to the procedure forCap-51.

Cap Structure LCMS Cap-117

LCMS: Anal. Calcd. for C₁₂H₁₅NO₄S: 237; found: 238(M + H)⁺. Cap-118

LCMS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244(M + H)⁺. Cap-119

LCMS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244(M + H)⁺. Cap-120

LCMS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244(M + H)⁺. Cap-121

¹HNMR(400 MHz, CDCl₃) δ 4.06-4.16(m, 1 H), 3.63(s, 3 H), 3.43(s, 1 H),2.82 and 2.66(s, br, 1 H), 1.86-2.10(m, 3 H), 1.64-1.76(m, 2 H), 1.44-1.53(m, 1 H). Cap-122

¹HNMR(400 MHz, CDCl₃) δ 5.28 and 5.12 (s, br, 1 H), 3.66(s, 3 H),2.64-2.74(m, 1 H), 1.86- 2.12(m, 3 H), 1.67- 1.74(m, 2 H), 1.39-1.54 (m,1 H). Cap-123

LCMS: Anal. Calcd. for C₂₇H₂₆N₂O₆: 474; found: 475(M + H)⁺.

Preparation of Cap-124. (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylicacid

The hydrochloride salt of L-threonine tert-butyl ester was carbamoylatedaccording to the procedure for Cap-51. The crude reaction mixture wasacidified with 1N HCl to pH˜1 and the mixture was extracted with EtOAc(2×50 mL). The combined organic phases were concentrated in vacuo togive a colorless which solidified on standing. The aqueous layer wasconcentrated in vacuo and the resulting mixture of product and inorganicsalts was triturated with EtOAc—CH₂Cl₂-MeOH (1:1:0.1) and then theorganic phase concentrated in vacuo to give a colorless oil which wasshown by LCMS to be the desired product. Both crops were combined togive 0.52 g of a solid. ¹HNMR (400 MHz, CD₃OD) δ 4.60 (m, 1H), 4.04 (d,J=5.0 Hz, 1H), 1.49 (d, J=6.3 Hz, 3H). LCMS: Anal. Calcd. for C₅H₇NO₄:145. found: 146 (M+H)⁺.

Preparation of Cap-125.(S)-2-(tert-butoxycarbonylamino)-4-(dimethylamino)butanoic acid

Cap-125 was prepared according to the procedure for the preparation ofCap-1. The crude product was used as is in subsequent reactions. LCMS:Anal. Calcd. for C₁₁H₂₂N₂O₄: 246. found: 247 (M+H)⁺.

Preparation of(S)-2-(methoxycarbonylamino)-3-(1-methyl-1H-imidazol-2-yl)propanoic acid(Cap-126)

This procedure is a modification of that used to prepare Cap-51. To asuspension of (S)-2-amino-3-(1-methyl-1H-imidazol-2-yl)propanoic acid(0.80 g, 4.70 mmol) in THF (10 mL) and H₂O (10 mL) at 0° C. was addedNaHCO₃ (0.88 g, 10.5 mmol). The resulting mixture was treated withClCO₂Me (0.40 mL, 5.20 mmol) and the mixture allowed to stir at 0° C.After stirring for ca. 2 h LCMS showed no starting material remaining.The reaction was acidified to pH 2 with 6 N HCl.

The solvents were removed in vacuo and the residue was suspended in 20mL of 20% MeOH in CH₂Cl₂. The mixture was filtered and concentrated togive a light yellow foam (1.21 g,). LCMS and ¹H NMR showed the materialto be a 9:1 mixture of the methyl ester and the desired product. Thismaterial was taken up in THF (10 mL) and H₂O (10 mL), cooled to 0° C.and LiOH (249.1 mg, 10.4 mmol) was added. After stirring ca. 1 h LCMSshowed no ester remaining. Therefore the mixture was acidified with 6NHCl and the solvents removed in vacuo. LCMS and ¹H NMR confirm theabsence of the ester. The title compound was obtained as its HCl saltcontaminated with inorganic salts (1.91 g, >100%). The compound was usedas is in subsequent steps without further purification.

¹HNMR (400 MHz, CD₃OD) δ 8.84, (s, 1H), 7.35 (s, 1H), 4.52 (dd, J=5.0,9.1 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (dd, J=4.5, 15.6 Hz, 1H,partially obscured by solvent), 3.12 (dd, J=9.0, 15.6 Hz, 1H).

LCMS: Anal. Calcd. for C₁₇H₁₅NO₂: 392. found: 393 (M+H)⁺.

Preparation of(S)-2-(methoxycarbonylamino)-3-(1-methyl-1H-imidazol-4-yl)propanoic acid(Cap-127)

Cap-127 was prepared according to the method for Cap-126 above startingfrom (S)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoic acid (1. II g,6.56 mmol), NaHCO₃ (1.21 g, 14.4 mmol) and ClCO₂Me (0.56 mL, 7.28 mmol).The title compound was obtained as its HCl salt (1.79 g, >100%)contaminated with inorganic salts. LCMS and ¹H NMR showed the presenceof ca. 5% of the methyl ester. The crude mixture was used as is withoutfurther purification.

¹HNMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.35 (s, 1H), 4.48 (dd, J=5.0,8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m, 1H), 3.08 (m, 1H).

LCMS: Anal. Calcd. for C₁₇H₁₅NO₂: 392. found: 393 (M+H)⁺.

Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid(Cap-128)

Step 1. Preparation of (S)-benzyl2-(tert-butoxycarbonylamino)pent-4-ynoate (cj-27b)

To a solution of cj-27a (1.01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol)and iPr₂NEt (1.7 mL, 9.8 mmol) in CH₂Cl₂ (100 mL) at 0° C. was addedCbz-Cl (0.68 mL, 4.83 mmol). The solution was allowed to stir for 4 h at0° C., washed (1N KHSO₄, brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (TLC 6:1 hex:EtOAc) to give the title compound (1.30 g,91%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 7.35 (s, 5H), 5.35 (d,br, J=8.1 Hz, 1H), 5.23 (d, J=12.2 Hz, 1H), 5.17 (d, J=12.2 Hz, 1H),4.48-4.53 (m, 1H), 2.68-2.81 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.44 (s,9H). LCMS: Anal. Calcd. for C₁₇H₂₁NO₄: 303. found: 304 (M+H)⁺.

Step 2. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(cj-28)

To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate(0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO₄-5H₂O(0.022 g, 0.09 mmol) and NaN₃ (0.13 g, 2.1 mmol) in DMF-H₂O (5 mL, 4:1)at rt was added BnBr (0.24 mL, 2.02 mmol) and the mixture was warmed to65° C. After 5 h LCMS indicated low conversion. A further portion ofNaN₃ (100 mg) was added and heating was continued for 12 h. The reactionwas poured into EtOAc and H₂O and shaken. The layers were separated andthe aqueous layer extracted 3× with EtOAc and the combined organicphases washed (H₂O×3, brine), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash (Biotage, 40+M 0-5% MeOHin CH₂Cl₂; TLC 3% MeOH in CH₂Cl₂) to afford a light yellow oil whichsolidified on standing (748.3 mg, 104%). The NMR was consistent with thedesired product but suggests the presence of DMF. The material was usedas is without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 7.84 (s,1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m, 1H), 3.16(dd, J=1.0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd, J=9.1,14.7 Hz, 1H), 1.31 (s, 9H).

LCMS: Anal. Calcd. for C₂₄H₂₈N₄O₄: 436. found: 437 (M+H)⁺.

Step 2. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(cj-29)

A solution of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(0.52 g, 1.15 mmol) in CH₂Cl₂ was added TFA (4 mL). The mixture wasallowed to stir at room temperature for 2 h. The mixture wasconcentrated in vacuo to give a colorless oil which solidified onstanding. This material was dissolved in THF—H₂O and cooled to 0° C.Solid NaHCO₃ (0.25 g, 3.00 mmol) was added followed by ClCO₂Me (0.25 mL,3.25 mmol). After stirring for 1.5 h the mixture was acidified to pH˜2with 6N HCl and then poured into H₂O-EtOAc. The layers were separatedand the aq phase extracted 2× with EtOAc. The combined org layers werewashed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuoto give a colorless oil (505.8 mg, 111%, NMR suggested the presence ofan unidentified impurity) which solidified while standing on the pump.The material was used as is without further purification. ¹HNMR (400MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.27-7.32 (m,10H), 5.54 (s, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H),4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J=5.6, 14.7 Hz, 1H), 2.98(dd, J=9.6, 14.7 Hz, 1H). LCMS: Anal. Calcd. for C₂₁H₂₂N₄O₄: 394. found:395 (M+H)⁺.

Step 3. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid(Cap-128)

(S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) inMeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filteredthrough diatomaceous earth (Celite®) and concentrated in vacuo.(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid wasobtained as a colorless gum (266 mg, 111%) which was contaminated withca. 10% of the methyl ester. The material was used as is without furtherpurification.

¹HNMR (400 MHz, DMSO-d₆) δ 12.78 (s, br, 1H), 7.59 9s, 1H), 7.50 (d,J=8.0 Hz, 1H), 4.19-4.24 (m, 1H), 3.49 (s, 3H), 3.12 (dd, J=4.8 Hz, 14.9Hz, 1H), 2.96 (dd, J=9.9, 15.0 Hz, 1H). LCMS: Anal. Calcd. forC₇H₁₀N₄O₄: 214. found: 215 (M+H)⁺.

Preparation of (S)-2-(methoxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoicacid (Cap-129)

Step 1. Preparation of(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (cj-31)

A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03mmol), and pyrazole (0.22 g, 3.29 mmol) in CH₃CN (12 mL) was heated at50° C. for 24 h. The mixture was cooled to rt overnight and the solidfiltered to afford(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1mg). The filtrate was concentrated in vacuo and then triturated with asmall amount of CH₃CN (ca. 4 mL) to afford a second crop (43.5 mg).Total yield 370.4 mg (44%).

m.p. 165.5-168° C. lit m.p. 168.5-169.5 Vederas et al. J. Am. Chem. Soc.1985, 107, 7105.

¹HNMR (400 MHz, CD₃OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H),7.24-7.34 (m, 5H), 6.23 m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J=12.7 Hz,1H), 4.59-4.66 (m, 2H), 4.42-4.49 (m, 1H). LCMS: Anal. Calcd. forC₁₄H₁₅N₃O₄: 289. found: 290 (M+H)⁺.

Step 2. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (Cap-129)

(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (0.20g, 0.70 mmol) was hydrogenated in the presence of Pd—C (45 mg) in MeOH(5 mL) at atmospheric pressure for 2 h. The product appeared to beinsoluble in MeOH, therefore the r×n mixture was diluted with 5 mL H₂Oand a few drops of 6N HCl. The homogeneous solution was filtered throughdiatomaceous earth (Celite®), and the MeOH removed in vacuo. Theremaining solution was frozen and lyophilized to give a yellow foam(188.9 mg). This material was suspended in THF—H₂O (1:1, mL) and thencooled to 0° C. To the cold mixture was added NaHCO₃ (146.0 mg, 1.74mmol) carefully (evolution of CO₂). After gas evolution had ceased (ca.15 min) ClCO₂Me (0.06 mL, 0.78 mmol) was added dropwise. The mixture wasallowed to stir for 2 h and was acidified to pH˜2 with 6N HCl and pouredinto EtOAc. The layers were separated and the aqueous phase extract withEtOAC (×5). The combined organic layers were washed (brine), dried(Na₂SO₄), filtered, and concentrated to give the title compound as acolorless solid (117.8 mg, 79%).

¹HNMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 7.63 (d, J=2.6 Hz, 1H), 7.48(d, J=8.1 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 6.19 (app t, J=2.0 Hz, 1H),4.47 (dd, J=3.0, 12.9 Hz, 1H), 4.29-4.41 (m, 2H), 3.48 (s, 3H). LCMS:Anal. Calcd. for C₈H₁₁N₃O₄: 213. found: 214 (M+H)⁺.

Cap-130 was prepared by acylation of commercially available(R)-phenylglycine analogous to the procedure given in: Calmes, M.;Daunis, J.; Jacquier, R.; Verducci, J. Tetrahedron, 1987, 43(10), 2285.

EXAMPLES

The present disclosure will now be described in connection with certainembodiments which are not intended to limit its scope. On the contrary,the present disclosure covers all alternatives, modifications, andequivalents as can be included within the scope of the claims. Thus, thefollowing examples, which include specific embodiments, will illustrateone practice of the present disclosure, it being understood that theexamples are for the purposes of illustration of certain embodiments andare presented to provide what is believed to be the most useful andreadily understood description of its procedures and conceptual aspects.

Solution percentages express a weight to volume relationship, andsolution ratios express a volume to volume relationship, unless statedotherwise. Nuclear magnetic resonance (NMR) spectra were recorded eitheron a Bruker 300, 400, or 500 MHz spectrometer; the chemical shifts (6)are reported in parts per million. Flash chromatography was carried outon silica gel (SiO₂) according to Still's flash chromatography technique(J. Org. Chem. 1978, 43, 2923).

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters Micromass ZQ MS system. It shouldbe noted that retention times may vary slightly between machines. The LCconditions employed in determining the retention time (RT) were:

Condition 1

Column=Phenomenex-Luna 3.0×50 mm S10

Start % B=0

Final % B=100

Gradient time=2 min

Stop time=3 min

Flow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition 2

Column=Phenomenex-Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient time=2 min

Stop time=3 min

Flow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition 3

Column=HPLC XTERRA C18 3.0×50 mm S7

Start % B=0

Final % B=100

Gradient time=3 min

Stop time=4 min

Flow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Method A: LCMS—Xterra MS C-18 3.0×50 mm, 0 to 100% B over 30.0 minutegradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Method B: HPLC—X-Terra C-18 4.6×50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90%methanol 10% water 0.1% TFA

Method C: HPLC—YMC C-18 4.6×50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.2% H₃PO₄, B=90%methanol 10% water 0.2% H₃PO₄.

Method D: HPLC—Phenomenex C-18 4.6×150 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.2% H₃PO₄, B=90%methanol 10% water 0.2% H₃PO₄

Method E: LCMS—Gemini C-18 4.6×50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Method F: LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minutegradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Example 1(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 1 Step a

N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g,33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of2-amino-1-(4-bromophenyl)ethanone (8.127 g, 32.44 mmol), and DMF (105mL), and stirred at ambient condition for 55 minutes. Most of thevolatile component was removed in vacuo, and the resulting residue waspartitioned between ethyl acetate (300 mL) and water (200 mL). Theorganic layer was washed with water (200 mL) and brine, dried (MgSO₄),filtered, and concentrated in vacuo. A silica gel mesh was prepared fromthe residue and submitted to flash chromatography (silica gel; 50-60%ethyl acetate/hexanes) to provide ketoamide 1a as a white solid (12.8g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 8.25-8.14 (m, 1H), 7.92 (brd, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53(dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23(m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s,9H). LC (Cond. 1): RT=1.70 min; LC/MS: Anal. Calcd. for [M+Na]⁺C₁₈H₂₃BrN₂NaO₄: 433.07. found 433.09.

Analogous compounds such as intermediate 1-1a to 1-5a can be prepared byincorporating the appropriately substituted amino acid and aryl bromideisomer.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35/1.40 (two br s, 9H), 2.27-2.42 (m,1H), 2.73-2.95 (m, 1H), 3.62-3.89 (m, 2H), 4.36-4.50 (m, 1H), 4.51-4.60(m, 1H), 4.62-4.73 (m, 1H), 7.75 (d, J=8.24 Hz, 2H), 7.92 (d, J=7.63 Hz,2H), 8.31-8.49 (m, 1H). HPLC XTERRA C-18 4.6×30 mm, 0 to 100% B over 4minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H₃PO₄,B=10% water, 90% methanol, 0.2% H₃PO₄, RT=1.59 minutes, 99% homogeneityindex. LCMS: Anal. Calcd. for C₁₈H₂₁BrF₂N₂O₄: 446.06. found: 445.43(M−H)⁻.

¹H NMR (500 MHz, DMSO-d₆) δ ppm (8.25 1H, s), 7.91 (2H, d, J=8.24 Hz),7.75 (2H, d, J=8.24 Hz), 4.98 (1H, s), 4.59-4.63 (1H, m), 4.46-4.52 (1H,m), 4.23 (1H, m), 3.37 (1H, s), 3.23-3.28 (1H, m), 2.06 (1H, m), 1.88(1H, s), 1.38 (3H, s), 1.33 (6H, s). LCMS—Phenomenex C-18 3.0×50 mm, 0to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA mobile phase,RT=3.34 minutes, Anal Calcd. for C₁₈H₂₃BrN₂O₅ 427.30. found 428.08(M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.30 (1H, s) 7.93-7.96 (2H, m) 7.76 (2Hd, J=8.24 Hz) 5.13 (1H, s) 4.66-4.71 (1H, m) 4.52-4.55 (1H, m) 4.17 (1H,m) 3.51 (1H, s) 3.16-3.19 (1H, m) 2.36 (1H, m) 1.78 (1H, s) 1.40 (s,3H), 1.34 (s, 6H). LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA,B=90% methanol 10% water 0.1% TFA, RT=3.69 minutes, Anal Calcd. forC₁₈H₂₃BrN₂O₅ 427.30. found 428.16 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.47 (m, 9H), 1.67-1.90 (m, 3H),2.00-2.20 (m, 1H), 3.23-3.30 (m, 1H), 3.34-3.44 (m, 1H), 4.16 (dd, 1H),4.57 (q, 2H), 7.51 (t, J=7.78 Hz, 1H), 7.86 (dd, J=7.93, 1.22 Hz, 1H),7.98 (d, J=7.63 Hz, 1H), 8.11 (s, 1H), 8.15-8.29 (m, 1H). LC/MS(M+Na)⁺=433.12/435.12.

LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10%water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. RT=1.93min; LRMS: Anal. Calcd. for C₁₉H₁₈BrN₂O₄ 418.05. found: 419.07 (M+H)⁺.

Example 1 Step b

A mixture of ketoamide 1a (12.8 g, 31.12 mmol) and NH₄OAc (12.0 g, 155.7mmol) in xylenes (155 mL) was heated in a sealed tube at 140° C. for 2hours. The volatile component was removed in vacuo, and the residue waspartitioned carefully between ethyl acetate and water, whereby enoughsaturated NaHCO₃ solution was added so as to make the pH of the aqueousphase slightly basic after the shaking of the biphasic system. Thelayers were separated, and the aqueous layer was extracted with anadditional ethyl acetate. The combined organic phase was washed withbrine, dried (MgSO₄), filtered, and concentrated in vacuo. The resultingmaterial was recrystallized from ethyl acetate/hexanes to provide twocrops of imidazole 1b as a light-yellow dense solid, weighing 5.85 g.The mother liquor was concentrated in vacuo and submitted to a flashchromatography (silica gel; 30% ethyl acetate/hexanes) to provide anadditional 2.23 g of imidazole 1b. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz):δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H),3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app brs, 9H). LC (Cond. 1): RT=1.71 min; >98% homogeneity index; LC/MS: Anal.Calcd. for [M+H]⁺ C₁₈H₂₃BrN₃O₂: 392.10. found 391.96; HRMS: Anal. Calcd.for [M+H]⁺ C₁₈H₂₃BrN₃O₂: 392.0974. found 392.0959

The optical purity of the two samples of 1b were assessed using thechiral HPLC conditions noted below (ee>99% for the combined crops;ee=96.7% for the sample from flash chromatography):

Column: Chiralpak AD, 10 um, 4.6×50 mm

Solvent: 2% ethanol/heptane (isocratic)

Flow rate: 1 mL/min

Wavelength: either 220 or 254 nm

Relative retention time: 2.83 minutes (R), 5.34 minutes (S)

Analogous compounds such as intermediates 1-1b to 1-4b can be preparedby incorporating the appropriate ketoamide.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17/1.40 (two br s, 9H), 2.50-2.74 (m,J=25.64 Hz, 1H), 2.84-3.07 (m, 1H), 3.88 (d, J=10.07 Hz, 2H), 5.03 (s,1H), 7.50 (d, J=8.55 Hz, 2H), 7.60 (s, 1H), 7.70 (d, J=8.55 Hz, 2H),12.10 (s, 1H). HPLC XTERRA C-18 4.6×30 mm, 0 to 100% B over 4 minutes, 1minute hold time, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water,90% methanol, 0.2% H₃PO₄, RT=1.59 minutes, 99% homogeneity index; LCMS:Anal. Calcd. for C₁₈H₂₀BrF₂N₃O₂: 428.27. found: 428.02 (M)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.89-11.99 (1H, m), 7.68 (2H, d, J=8.54Hz), 7.52-7.59 (1H, m), 7.48 (2H, d, J=8.54 Hz), 4.80 (1H, m), 4.33 (1H,s), 3.51-3.60 (1H, m), 3.34 (1H, d, J=10.99 Hz), 2.14 (1H, s), 1.97-2.05(1H, m), 1.37 (3H, s), 1.10 (6H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (RT=3.23 min)Anal Calcd. for C₁₈H₂₂BrN₃O₃ 408.30. found 409.12 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.06-12.24 (1H, m), 7.58-7.69 (5H, m),4.84-4.95 (1H, m), 4.34 (1H, s), 3.61 (1H, s), 3.34-3.40 (1H, m), 2.52(1H, s), 1.92-2.20 (1H, m), 1.43 (3H, s), 1.22 (6H, s); LCMS—PhenomenexC-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute holdtime, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1%TFA, (RT=3.41 min) Anal Calcd. for C₁₈H₂₂BrN₃O₃ 408.30. found 409.15(M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98-1.51 (m, 9H), 1.82-2.12 (m, 3H),2.31-2.48 (m, 1H), 3.30-3.51 (m, 1H), 3.52-3.66 (m, 1H), 4.88-5.16 (m,1H), 7.47 (t, J=7.93 Hz, 1H), 7.61 (d, J=7.93 Hz, 1H), 7.81 (d, J=7.93Hz, 1H), 8.04 (s, 1H), 8.12 (d, J=28.38 Hz, 1H), 14.65 (s, 1H). LC/MS(M+H)⁺=391.96/393.96.

Additional imidazole analogs made following procedures similar to thosedescribed above.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Structure Data 1-5b

RT = 1.70 minutes (condition 2, 98%); LRMS: Anal. Calcd. forC₁₉H₁₈BrN₃O₂ 399.05; found: 400.08(M + H)⁺. 1-6b

RT = 1.64 minutes (condition 2, 98%); LRMS: Anal. Calcd. for C₁₇H₂₂N₃O₂379.09; found: 380.06(M + H)⁺. 1-7b

RT = 2.28 minutes (95%); LRMS: Anal. Calcd. for C₂₀H₂₁BrN₃O₂ 414.08;found: 414.08 (M + H)⁺; HRMS: Anal. Calcd. for C₂₀H₂₁BrN₃O₂ 414.0817;found: 414.0798(M + H)⁺.

Example 1 Step c

Pd(Ph₃P)₄ (469 mg, 0.406 mmol) was added to a pressure tube containing amixture of bromide 1b (4.008 g, 10.22 mmol), bis(pinacolato)diboron(5.422 g, 21.35 mmol), potassium acetate (2.573 g, 26.21 mmol) and1,4-dioxane (80 mL). The reaction flask was purged with nitrogen, cappedand heated with an oil bath at 80° C. for 16.5 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Thecrude material was partitioned carefully between CH₂Cl₂ (150 mL) and anaqueous medium (50 mL water+10 mL saturated NaHCO₃ solution). Theaqueous layer was extracted with CH₂Cl₂, and the combined organic phasewas dried (MgSO₄), filtered, and concentrated in vacuo. The resultingmaterial was purified with flash chromatography (sample was loaded witheluting solvent; 20-35% ethyl acetate/CH₂Cl₂) to provide boronate 1c,contaminated with pinacol, as an off-white dense solid; the relativemole ratio of 1c to pinacol was about 10:1 (¹H NMR). The sample weighed3.925 g after ˜2.5 days exposure to high vacuum. ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): 12.22/11.94/11.87 (m, 1H), 7.79-7.50/7.34-7.27 (m, 5H),4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.27-1.77 (m, 4H),1.45-1.10 (m, 21H). LC (Cond. 1): RT=1.64 min; LC/MS: Anal. Calcd. for[M+H]⁺ C₂₄H₃₅BN₃O₄: 440.27. found 440.23.

Analogous compounds such as intermediates 1-1c to 1-4c can be preparedby incorporating the appropriate aryl bromide.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (s, 8H), 1.29 (s, 13H), 2.51-2.72(m, 1H), 2.84-3.03 (m, 1H), 3.79-4.00 (m, 2H), 4.88-5.21 (m, 1H), 7.62(d, J=7.93 Hz, 2H), 7.67 (s, 1H), 7.76 (d, J=7.93 Hz, 2H), 12.11/12.40(two br s, 1H). HPLC GEMINI C-18 4.6×50 mm, 0 to 100% B over 4 minutes,1 minute hold time, A=95% water, 5% acetonitrile, 0.1% NH₄OAc, B=5%water, 95% acetonitrile, 0.1% NH₄OAc, RT=1.62 minutes, 99% homogeneityindex. LCMS: Anal. Calcd. for C₃₄H₃₂BF₂N₃O₄: 475.34. found: 474.78(M−H)⁻.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.97 (1H, m), 7.62-7.75 (5H, m), 5.05(1H d, J=3.36 Hz), 4.82 (m, 1H), 4.35 (m, 1H), 3.58 (1H, m), 2.389 (1H,s), 2.17 (1H, m), 1.38 (3H, s), 1.30 (12H, s), 1.1 (6H, s);LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate,B=95% acetonitrile, 5% water, 10 mm ammonium acetate, RT=3.63 minutes,Anal. Calcd. for C₂₄H₃₄BN₃O₅ 455.30. found 456.31 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05-12.24 (1H, m), 7.61-7.73 (5H, m),4.83-5.01 (1H, m), 4.33 (1H, s), 3.54-3.63 (1H, m), 3.39-3.80 (1H, m),2.38-2.49 (1H, m), 1.98-2.01 (1H, m), 1.42 (3H, s), 1.34 (12H, s), 1.21(6H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90%methanol 10% water 0.1% TFA, RT=3.64 minutes, Anal. Calcd. forC₂₄H₃₄BN₃O₅ 455.30. found 456.30 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02-1.54 (m, 21H), 1.75-2.07 (m, 3H),2.09-2.33 (m, 1H), 3.32-3.44 (m, 1H), 3.55 (s, 1H), 4.69-4.94 (m, 1H),7.33 (t, J=7.32 Hz, 1H), 7.41-7.57 (m, 2H), 7.84 (d, J=7.32 Hz, 1H),8.08 (s, 1H), 11.62-12.07 (m, 1H). LC/MS (M+H)⁺=440.32.

Additional boronic esters: Conditions for 1-5c through 1-10c

LCMS conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100%B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1%TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

1-5c

RT = 1.84 minutes (condition 2); LCMS: Anal. Calcd. for C₂₇H₃₂BN₃O₄ 473;found: 474(M + H)⁺. 1-6c

RT = 1.84 minutes (condition 2); LCMS: Anal. Calcd. for C₂₂H₃₂BN₃O₄ 413;found: 414(M + H)⁺. 1-7c

RT = 1.85 minutes (condition 2); LRMS: Anal. Calcd. for C₂₅H₃₁BN₃O₄ 448;found: 448(M + H)⁺. 1-8c

RT = 2.49(76%, boronic ester) and 1.81(21.4%, boronic acid); LCMS: Anal.Calcd. for C₂₃H₃₅N₃O₄B 428.27; found: 428.27(M + H)⁺; HRMS: Anal. Calcd.for C₂₃H₃₅N₃O₄B 428.2721; found: 428.2716(M + H)⁺. 1-9c

RT = 2.54(74.2%, boronic ester) and 1.93 (25.8%, boronic acid); LRMS:Anal. Calcd. for C₂₆H₃₃N₃O₄B 462.26; found: 462.25(M + H)⁺; HRMS: Anal.Calcd. for C₂₆H₃₃N₃O₄B 462.2564; found: 462.2570(M + H)⁺. 1-10c

RT = 1.91(64.5%, boronic ester) and 1.02 (33.8%, boronic acid); LRMS:Anal. Calcd. for C₂₆H₃₂N₄O₃ ¹⁰B 458.26; found: 458.28(M + H)⁺; HRMS:Anal. Calcd. for C₂₆H₃₂N₄O₃ ¹⁰B 458.2604; found: 458.2617(M + H)⁺.

Example 1 Step d di-tert-butyl(2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

Pd(Ph₃P)₄ (59.9 mg, 0.0518 mmol) was added to a mixture of bromide 1b(576.1 mg, 1.469 mmol), boronate 1c (621.8 mg, 1.415 mmol), NaHCO₃(400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL).The reaction mixture was flushed with nitrogen, heated with an oil bathat 80° C. for 5.75 hours, and then the volatile component was removed invacuo. The residue was partitioned between 20% methanol/CHCl₃ (60 mL)and water (30 mL), and the aqueous phase was extracted with 20%methanol/CHCl₃ (30 mL). The combined organic phase was washed withbrine, dried (MgSO₄), filtered, and concentrated in vacuo. A silica gelmesh was prepared from the resulting crude material and submitted toflash chromatography (ethyl acetate) to provide dimer 1d, contaminatedwith Ph₃PO, as an off-white solid (563 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz): δ 12.21-12-16/11.95-11.78 (m, 2H), 7.85-7.48/7.32-7.25 (m,10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.46-1.10(m, 18H). LC (Cond. 1b): RT=1.77 min; LC/MS: Anal. Calcd. for [M+H]⁺C₃₆H₄₅BN₆O₄: 625.35. found 625.48.

Additional symmetric analogs can be prepared in similar fashion.

Example 1-1d was prepared using intermediates 1-2c and 1-2b. ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.94-12.22 (2H, m) 7.53-7.82 (10H, m) 4.82-4.92(2H, m) 4.34-4.43 (2H, m) 3.55-3.64 (2H, m) 3.36 (2H, d, J=11.29 Hz)2.12-2.22 (2H, m) 2.02-2.11 (2H, m) 1.40 (6H, s) 1.14 (12H, s);LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10%water 0.1% TFA, RT=3.32 min, Anal. Calcd. for 656.79. found 657.40(M+H)⁺. Nominal/LRMS-(M+H)⁺⁻657.42, (M−H)⁻ 655.28.

Example 1-2d was prepared using intermediates 1-3b and 1-3c. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.00-12.20 (2H, m) 7.56-7.76 (10H, m) 4.90 (1H, s)4.82 (1H, s) 4.25-4.34 (2H, m) 3.56 (2H, s) 3.34-3.47 (2H, m) 1.97-2.13(4H, m) 1.39 (9H, m) 1.20 (9H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90%water 0.1% TFA, B=90% methanol 10% water 0.1% TFA; RT=3.35 min, Anal.Calcd. for 656.79. found 657.30 (M+H)⁺.

tert-butyl(2S)-2-(4-(3′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

Example 1-2d-1 was prepared using intermediates 1-4c and 1-4b. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.09-1.51 (m, 18H), 1.84-2.15 (m, 6H),2.34-2.50 (m, 2H), 3.35-3.52 (m, 2H), 3.54-3.67 (m, 2H), 5.08 (d, J=5.49Hz, 2H), 7.68 (t, J=7.78 Hz, 2H), 7.78-7.92 (m, 4H), 8.11-8.30 (m, 4H),14.81 (s, 2H). LC/MS (M+H)⁺=625.48.

Diol 1-1d (0.15 g, 0.23 mmol) was added as a solid to a solution ofbis(2-methoxyethyl)aminosulfur trifluoride (0.1 mL, 0.51 mmol) in 11.0mL CH₂Cl₂ cooled to −78° C. The reaction was stirred at −78° C. for twohours and then warmed to room temperature and stirred for 2 hours. Thereaction was poured into saturated sodium bicarbonate solution andstirred until bubbling ceased. The layers were separated and the aqueouslayer was extracted one time with CH₂Cl₂. The combined organics werewashed with brine, dried (MgSO₄), filtered, and concentrated to give ayellow oil. The oil was triturated with CH₂Cl₂ and pentane to providethe desired product as a tan solid (0.092 g, 61%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.76-11.94 (2H, m), 7.77-7.85 (4H, m), 7.66-7.72 (4H,m), 7.60-7.66 (2H, m, J=11.60 Hz), 5.39 (1H, s), 5.28 (1H, s), 5.03 (2H,s), 3.66-3.79 (4H, m), 2.61-2.70 (2H, m), 2.28-2.38 (2H, m), 1.42 (10H,s), 1.24 (8H, s). LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA,B=90% methanol 10% water 0.1% TFA, (t_(R)=3.58 min) Anal Calcd. forC₃₆H₄₂F₂N₆O₄ 660.70. found 661.68 (M+H)⁺.

Prepared from 1-1b and 1-1c in the same manner as the preparation of 1dfrom 1b and 1c. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.18/1.40 (two br. s.,18H), 2.53-2.75 (m, J=25.94 Hz, 2H), 2.86-3.06 (m, 2H), 3.78-4.02 (m,4H), 5.04 (br s, 2H), 7.17-8.24 (m, 10H), 12.07/12.37 (two br. s., 2H);HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minutes holdtime, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water, 90% methanol,0.2% H₃PO₄, RT=1.31 min, 99% homogeneity index. LCMS: Anal. Calcd. forC₃₆H₄₀F₄N₆O₄: 696.73. found: 967.64 (M+H)⁺.

Dissymmetric compounds such as intermediate 1-3d and 1-4d can beprepared by the same method. For example, reaction of 1-1c with 1b inthe same manner as described above for the preparation of 1d provided1-3d. Similarly, reaction of 1-4c with 1b in the same manner asdescribed above for the preparation of 1d provided 1-4d.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40/1.18 (two br s, 18H), 1.90-2.02 (m,2H), 2.02-2.12 (m, 1H), 2.28-2.46 (m, 2H), 2.68-2.87 (m, 1H), 3.35-3.49(m, 1H), 3.53-3.62 (m, 1H), 3.82-4.10 (m, 2H), 4.92-5.11 (m, 1H), 5.28(s, 1H), 7.79-8.00 (m, 8H), 8.03-8.25 (m, 2H), 13.77-15.16 (m, 2H); HPLCXTERRA C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time,A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2%H₃PO₄, RT=1.22 minutes, 99% homogeneity index. LCMS: Anal. Calcd. forC₃₆H₄₂F₂N₆O₄: 660.75. found: 661.98 (M+H)⁺.

Example 1-4d was prepared from 1-4c and 1b in similar fashion to thepreparation of 1d from 1b and 1c. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.99-1.60 (m, 18H) 1.75-2.11 (m, J=73.24 Hz, 6H) 2.12-2.32 (m, 2H)3.32-3.41 (m, 2H) 3.56 (s, 2H) 4.63-5.02 (m, 2H) 6.98-8.28 (m, 10H)11.67-12.33 (m, 2H); LC conditions: Phenomenex Luna 3.0×5.0 mm S10,Solvent A—0.1% TFA in 10% MeOH/90% H₂O, Solvent B—0.1% TFA in 90%MeOH/10% H₂O, 0 to 100% B over 2 min, Stop time=3 min, Flow rate=4ml/min, Wavelength=220 nm, LC/MS (M+H)⁺=625.32. Retention time=1.438 min

Additional biphenyl analogs were prepared similarly.

LC conditions for Examples 1-5d through 1-7d: Condition 1: PhenomenexLUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time,A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1%TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Characterization Example Compound Name Structure Data 1-5ddi-tert-butyl(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(1S)-1,1-ethanediyl))bis(meth ylcarbamte)

RT = 1.64 minutes (>95%); Condition 2; LCMS: Anal. Calcd C₃₄H₄₅N₆O₄601.35; found: 601.48(M + H)⁺; LRMS: Anal. Calcd. for C₃₄H₄₄N₆O₄ 600.34;found: 601.32(M + H)⁺. 1-6d tert-butyl (2S)-2-(5- (4′-(2-((1S)-1-((tert-butoxycarbonyl)(meth- yl)amino)ethyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate

RT = 1.63 minutes (>95%); Condition 2; LCMS: Anal. Calcd C₃₅H₄₅N₆O₄613.34; found: 613.56(M + H)⁺; LRMS: Anal. Calcd. for C₃₅H₄₄N₆O₄ 612.34;found: 613.33(M + H)⁺. 1-7d benzyl (2S)-2-(5-(4′- (2-((1S)-1-((tert-butoxycarbonyl)(meth- yl)amino)ethyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate

RT = 1.65 minutes (>95%); Condition 2; LCMS: Anal. Calcd C₃₈H₄₃N₆O₄647.33; found: 647.44(M + H)⁺; LRMS: Anal. Calcd. for C₃₈H₄₂N₆O₄ 646.33;found: 647.34(M + H)⁺.

Example 1 Step e5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)

A mixture of carbamate 1d (560 mg) and 25% TFA/CH₂Cl₂ (9.0 mL) wasstirred at ambient condition for 3.2 hours. The volatile component wasremoved in vacuo, and the resulting material was free based using an MCXcolumn (methanol wash; 2.0 M NH₃/methanol elution) to providepyrrolidine 1e as a dull yellow solid (340 mg). ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): δ 11.83 (br s, 2H), 7.80 (d, J=8.1, 4H), 7.66 (d, J=8.3,4H), 7.46 (br s, 2H), 4.16 (app t, J=7.2, 2H), 2.99-2.69 (m, 6H),2.09-2.00 (m, 2H), 1.94-1.66 (m, 6H). LC (Cond. 1): RT=1.27 min; >98%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₆H₂₉N₆: 425.25.found 425.25; HRMS: Anal. Calcd. for [M+H]⁺ C₂₆H₂₉N₆: 425.2454. found425.2448

Additional analogs such as 1-1e to 1-4e can be prepared in a similarfashion.

To a solution of 1-1d (3R,3′R,5S,5′S)-tert-butyl5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-1-carboxylate)in 3 mL dioxane was added 0.8 mL of a 4.0M solution of HCl in dioxane.The reaction was stirred for 2 hours at room temperature andconcentrated under reduced pressure. The resulting tan solid was driedunder vacuum to give 1-1e(3R,3′R,5S,5′S)-5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidin-3-oltetrahydrochloride(0.55 g, 100% yield). Used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 10.33 (s, 2H), 9.85 (s, 2H), 8.09 (s, 2H), 8.01 (d,J=8.24 Hz, 4H), 7.88 (d, J=8.24 Hz, 4H), 5.14 (m, 2H), 4.62 (m, 2H),3.61 (m, 2H), 3.23 (d, J=11.29 Hz, 2H), 2.64 (m, 2H), 2.44 (dd, J=13.43,6.71 Hz, 2H); LCMS—Waters-Sunfire C-18 4.6×50 mm, 0 to 100% B over 4.0minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA,B=90% methanol 10% water 0.1% TFA, RT=1.35 minutes Anal. Calcd. for456.30. found 457.25 (M+H)⁺; Nominal/LRMS-(M+H)⁺⁻457.35.

Example 1-2e was prepared in similar fashion to the method described forthe preparation of 1-1e. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.32 (1H, s)8.01 (2H, s) 7.97 (4H, d, J=8.24 Hz) 7.86 (4H, d, J=8.24 Hz) 5.01-5.10(2H, m) 4.52-4.60 (2H, m) 3.36-3.45 (2H, m) 3.25 (2H, s) 2.60-2.68 (2H,m) 2.40-2.48 (2H, m); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1%TFA, B=90% methanol 10% water 0.1% TFA, RT=2.10 min., Anal. Calcd. for456.30. found 457.22 (M+H)⁺

2-((2S)-2-pyrrolidinyl)-4-(3′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-biphenylyl)-1H-imidazole

Example 1-2e-1 was prepared from 1-2d-1 in similar fashion described forthe preparation of 1-1e. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.74-2.44 (m,12H), 4.83 (s, 2H), 7.37-7.72 (m, 4H), 7.74-8.03 (m, 4H), 8.10 (s, 2H),9.14 (s, 2H), 9.81 (s, 2H). LC/MS (M+H)⁺=425.30.

To a solution of 1-2d-2 (0.084 g, 0.13 mmol) in 1 mL dioxane was added0.5 mL of a 4.0M solution of HCl in dioxane. The reaction was stirredfor 2 hours at room temperature and concentrated under reduced pressure.The resulting tan solid was dried under vacuum to give 1-2e-2 (0.077 g,100% yield). The compound was used without further purification. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.00 (2H, s), 7.97 (4H, d, J=8.55 Hz), 7.85(4H, d, J=8.24 Hz), 5.63 (1H, s), 5.52 (1H, s), 5.09-5.17 (2H, m),3.67-3.74 (2H, m), 3.63-3.67 (2H, m), 3.07-3.14 (1H, m), 2.89-2.96 (1H,m), 2.81-2.87 (2H, m); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1%TFA, B=90% methanol 10% water 0.1% TFA, (t_(R)=222 min) Anal Calcd. forC₂₆H₂₆F₂N₆ 460.53. found 461.37 (M+H)⁺.

Prepared from 1-2d-3 in the same manner as the preparation of 1-1e from1-1d. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.97-3.13 (m, 4H), 3.64-3.91 (m,4H), 5.16 (d, J=6.41 Hz, 2H), 7.84 (d, J=7.93 Hz, 4H), 7.96 (d, J=7.93Hz, 4H), 8.00 (s, 2H); HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 4minutes, 1 minutes hold time, A=90% water, 10% methanol, 0.2% H₃PO₄,B=10% water, 90% methanol, 0.2% H₃PO₄, RT=1.66 min, 92% homogeneityindex. LCMS: Anal. Calcd. for C₂₆H₂₄F₄N₆: 496.50. found: 495.53 (M−H)⁻.

Analogous dissymmetric compounds such as intermediates 1-3e and 1-4e canbe prepared by the same method.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.87-2.09 (m, 1H), 2.13-2.26 (m, 1H),2.37-2.47 (m, 2H), 2.92-3.12 (m, 2H), 3.37 (s, 1H), 3.40-3.49 (m, 1H),3.67-3.91 (m, 2H), 4.96-5.05 (m, 1H), 5.14 (t, J=8.70 Hz, 1H), 7.86 (t,J=9.00 Hz, 4H), 7.93-8.03 (m, 5H), 8.10 (s, 1H), 10.26/9.75 (two br s.,2H); HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minutehold time, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water, 90%methanol, 0.2% H₃PO₄, RT=0.8622 minutes, 99% homogeneity index; LCMS:Anal. Calcd. for C₂₆H₂₆F₂N₆: 460.52. found: 461.45 (M+H)⁺.

Example 1-4e was prepared from 1-4d in similar fashion to that describedfor the preparation of 1-1e from 1-1d. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.90-2.13 (m, 2H) 2.12-2.31 (m, 2H) 2.36-2.60 (m, 4H) 3.29-3.55 (m, 4H)5.00 (s, 2H) 7.35-8.50 (m, 10H) 9.76 (s, 2H) 10.12-10.45 (m, 2H). LCconditions: Phenomenex Luna 3.0×5.0 mm S10, Solvent A—0.1% TFA in 10%MeOH/90% H₂O, Solvent B—0.1% TFA in 90% MeOH/10% H₂O, 0 to 100% B over 2min, Stop time=3 min, Flow rate=4 ml/min, Wavelength=220 nm, LC/MS(M+H)⁺=425.28. Retention time=0.942 min

Additional analogs were prepared similarly:

Example Compound Name Structure Data 1-5e

RT = 1.37 min; LCMS: Anal. Calcd. for C₂₅H₂₈N₆ 412; found: 413 (M + H)⁺.1-6e

RT = 1.43 min; LCMS: Anal. Calcd. for C₃₃H₃₅N₆O₂ 547; found: 547 (M +H)⁺. 1-7e

RT = 1.12 min; LRMS: Anal. Calcd. for C₂₄H₂₈N₆ 400.24; found: 401.22(M + H)⁺. LC Conditions for 1-5e through 1-7e; Phenomenex LUNA C-18 4.6× 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water,10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220 nm, 5μL injection volume.

Alternative Synthesis of Example 1 Step e5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)

Example A-1e-1

A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overheadstirrer and thermocouple was charged with 20 g (83.9 mmol, 1 equiv)1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL CH₂Cl₂ and 8.7 mL (27.1 g,169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir undernitrogen for about 20 h under ambient conditions. The resulting slurrywas charged with 200 mL CH₂Cl₂ and concentrated down to about 150 mL viavacuum distillation. The slurry was then solvent exchanged into THF to atarget volume of 200 mL via vacuum distillation. The slurry was cooledto 20-25° C. over 1 h and allowed to stir at 20-25° C. for an additionalhour. The off-white crystalline solids were filtered and washed with 150mL CH₂Cl₂. The product was dried under vacuum at 60° C. to provide 27.4g (69.2 mmol, 82%) of the desired product: ¹H NMR (400 MHz, CDCl₃) δ7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); ¹³C NMR (100 MHz,CDCl₃) δ 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm⁻¹) 3007,2950, 1691, 1599, 1199; Anal calcd for C₁₆H₁₂Br₂O₂: C, 48.52; H, 3.05;Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd forC₁₆H₁₃Br₂O₂ (M+H; DCI⁺): 394.9282. Found: 394.9292. mp 224-226° C.

Example A-1e-2

A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple andoverhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of ExampleA-1e-1, 22.8 g (105.9 moles, 2.10 equiv)1-(tert-butoxycarbonyl)-L-proline, and 200 mL acetonitrile. The slurrywas cooled to 20° C. followed by the addition of 18.2 mL (13.5 g, 104.4mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25° C. and allowed tostir for 3 h. The resulting clear, organic solution was washed with3×100 mL 13 wt % aqueous NaCl. The rich acetonitrile solution wassolvent exchanged into toluene (target volume=215 mL) by vacuumdistillation until there was less than 0.5 vol % acetonitrile.

Example A-1e-3

The above toluene solution of Example A-1e-2 was charged with 78 g(1.011 moles, 20 equiv) ammonium acetate and heated to 95-100° C. Themixture was allowed to stir at 95-100° C. for 15 h. After reactioncompletion, the mixture was cooled to 70-80° C. and charged with 7 mLacetic acid, 40 mL n-butanol, and 80 mL of 5 vol % aqueous acetic acid.The resulting biphasic solution was split while maintaining atemperature>50° C. The rich organic phase was charged with 80 mL of 5vol % aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol whilemaintaining a temperature>50° C. The resulting biphasic solution wassplit while maintaining a temperature>50° C. and the rich organic phasewas washed with an additional 80 mL of 5 vol % aqueous acetic acid. Therich organic phase was then solvent exchanged into toluene to a targetvolume of 215 mL by vacuum distillation. While maintaining atemperature>60° C., 64 mL MeOH was charged. The resulting slurry washeated to 70-75° C. and aged for 1 h. The slurry was cooled to 20-25° C.over 1 h and aged at that temperature for an additional hour. The slurrywas filtered and the cake was washed with 200 mL 10:3 toluene:MeOH. Theproduct was dried under vacuum at 70° C., resulting in 19.8 g (31.7mmol, 63%) of the desired product: ¹H NMR (400 MHz, DMSO-d₆) δ13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s,2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1(m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); ¹³CNMR (100 MHz, DMSO-d₆) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5,55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr,cm⁻¹) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C₃₆H₄₅N₆O₄(M+H; ESI⁺): 625.3502. Found: 625.3502. mp 190-195° C. (decomposed).

Example A-1e-4

To a 250 ml reactor equipped with a nitrogen line and overhead stirrer,25.0 g of Example A-1e-3 (40.01 mmol, 1 equiv) was charged followed by250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous hydrogenchloride. The temperature was increased to 50° C. and agitated at 50° C.for 5 h. The resulting slurry was cooled to 20-25° C. and held withagitation for ca. 18 h. Filtration of the slurry afforded a solid whichwas washed successively with 100 ml 90% methanol/water (V/V) and 2×100ml of methanol. The wet cake was dried in a vacuum oven at 50° C.overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

Recrystallization of Example A-1e-4

To a 250 ml reactor equipped with a nitrogen line and an overheadstirrer, 17.8 g of crude Example A-1e-4 was charged followed by 72 mLmethanol. The resulting slurry was agitated at 50° C. for 4 h, cooled to20-25° C. and held with agitation at 20-25° C. for 1 h. Filtration ofthe slurry afforded a crystalline solid which was washed with 60 mlmethanol. The resulting wet cake was dried in a vacuum oven at 50° C.for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the desired product: ¹HNMR (400 MHz, DMSO-d₆) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19(s, 2H), 7.05 (d, J=8.4, 4H), 7.92 (d, J=8.5, 4H), 5.06 (m, 2H),3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H);¹³C NMR (100 MHz, DMSO-d₆) δ 156.6, 142.5, 139.3, 128.1, 127.5, 126.1,116.9, 53.2, 45.8, 29.8, 24.3; IR (KBr, cm⁻¹) 3429, 2627, 1636, 1567,1493, 1428, 1028. Anal calcd for C₂₆H₃₂N₆Cl₄: C, 54.75; H, 5.65; Cl,24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39.Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9. mp 240° C.(decomposed)

Example 1(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

HATU (44.6 mg, 0.117 mmol) was added to a mixture of pyrrolidine 1e(22.9 mg, 0.054 mmol), diisopropylethylamine (45 μL, 0.259 mmol) andCap-1 (28.1 mg, 0.13 mmol) in DMF (1.5 mL), and the resulting mixturewas stirred at ambient for 90 minutes. The volatile component wasremoved in vacuo, and the residue was purified first by MCX (methanolwash; 2.0 M NH₃/methanol elution) and then by a reverse phase HPLCsystem (H₂O/methanol/TFA) to provide the TFA salt of Example 1 as anoff-white foam (44.1 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 10.25(br s, 2H), 8.20-7.10 (m, 20H), 5.79-5.12 (m, 4H), 4.05-2.98 (m, 4H),2.98-2.62 (m, 6H), 2.50-1.70 (m, 14H), [Note: the signal of theimidazole NH was too broad to assign a chemical shift]; LC (Cond. 1):RT=1.40 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₆H₅₁N₈O₂: 747.41. found 747.58

Examples 2 to 24-4d

Examples 2 to 24-4 h were prepared as TFA salts by substituting therespective acids for Cap-1 using the same method described forExample 1. Caps in the following table without a number are commerciallyavailable.

Example Compound Name

RT(LC-Cond.); % homogeneity index; MS data 2 (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(2-oxo-1- phenylethanol)

1.55 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₆O₄: 693.32; found 693.46; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₆O₄: 693.3189; found 693.3182 3 (2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(1-oxo-2- phenyl-2-propanol)

1.77 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₄: 721.35; found 721.52; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₄: 721.3502; found 721.3515 4 dimethyl (4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))biscarbamate

1.64 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₄₇N₈O₆: 807.36; found 807.58 5 (1S,1′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N- dimethyl-2-oxo-1- phenylethanamine)

1.33 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₅₁N₈O₂: 747.41; found 747.64; HRMS: Anal. Calcd. for [M + H]⁺C₄₆H₅₁N₈O₂: 747.4135; found 747.4103 6 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-benzoyl-2- pyrrolidinyl)-1H-imidazole)

1.65 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₃₇N₆O₂: 633.30; found 633.51 7 5,5′-(4,4′-biphenyldiyl)bis(2-((2)S-1-(phenylacetyl)-2- pyrrolidinyl)-1H-imidazole)

1.71 minutes(Cond. 1); >98%; LCMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₁N₆O₂:661.33; found 661.53; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₁N₆O₂:661.3291; found 661.3300 8 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-((2R)-2-methoxy-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidaozle)

1.63 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₄: 721.35; found 721.59; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₄: 721.3502; found 721.3536 9 (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(1-oxo-3- phenyl-2-propanol)

1.71 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₄: 721.35; found 721.58; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₄: 721.3502; found 721.3497 10 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-propionyl-2- pyrrolidinyl)-1H-imidazole)

1.47 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₂H₃₇N₆O₂: 537.30; found 537.40; HRMS: Anal. Calcd. for [M + H]⁺C₃₂H₃₇N₆O₂: 537.2978; found 537.2952 11 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-(cyclopropylcarbonyl)- 2-pyrrolidinyl)-1H-imidazole)

1.48 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₄H₃₇N₆O₂: 561.30; found 561.44 12 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-(cyclopropylacetyl)-2- pyrrolidinyl)-1H-imidazole)

1.57 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₆H₄₁N₆O₂: 589.33; found 589.48; HRMS: Anal. Calcd. for [M + H]⁺C₃₆H₄₁N₆O₂: 589.3291; found 589.3268 13 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazole)

1.44 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₆H₄₁N₆O₄: 621.32; found 621.52; HRMS: Anal. Calcd. for [M + H]⁺C₃₆H₄₁N₆O₄: 621.3189; found 621.3191 14 2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N-dimethyl-2-oxoethanamine)

1.27 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₄H₄₃N₈O₂: 595.35; found 595.54; HRMS: Anal. Calcd. for [M + H]⁺C₃₄H₄₃N₈O₂: 595.3509; found 595.3503 15 (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(1-oxo-2- propanol)

1.36 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₂H₃₇N₆O₄: 569.29; found 569.44; HRMS: Anal. Calcd. for [M + H]⁺C₃₂H₃₇N₆O₄: 569.2876; found 569.2872 16 (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(3-methyl- 1-oxo-2-butanol)

1.51 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₆H₄₅N₆O₄: 625.35; found 625.50; HRMS: Anal. Calcd. for [M + H]⁺C₃₆H₄₅N₆O₄: 625.3517 17 5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazole)

1.13 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₅N₈O₂: 799.45; found 799.67 18 4,4′-(4,4′-biphenyldiylbis(1H-imidaozle-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))dimorpholine

1.11 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₅N₈O₄: 831.44; found 831.71 19 5,5′-(4,4′-biphenyldiyl)bis(2-((2)S-1-(((3S)-3-fluoro-1- pyrrolidinyl)(phenyl)acetyl)-2-pyrrolidinyl)-1H-imdiazole)

1.17 minutes(Cond. 1); 97%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₃F₂N₈O₂: 835.43; found 835.51; HRMS: Anal. Calcd. for [M + H]⁺C₅₀H₅₃F₂N₈O₂: 835.4260; found 835.4261 20 5,5′-(4,4′-biphenyldiyl)bis(2-((2)S-1-(((3S)-3-fluoro-1- pyrrolidiny)(phenyl)acetyl)-2-pyrrolidinyl)-1H-imidazole)

1.03 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₃F₂N₈O₂: 835.43; found 835.51; HRMS: Anal. Calcd. for [M + H]⁺C₅₀H₅₃F₂N₈O₂: 835.4260; found 835.4261 21 (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N- diethyl-2-oxo-1- phenylethanamine)

1.13 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₉N₈O₂: 803.48; found 803.56; HRMS: Anal. Calcd. for [M + H]⁺C₅₀H₅₉N₈O₂: 803.4761; found 803.4728 22 (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinedyl))bis(N-ethyl- N-methyl-2-oxo-1- phenylethanamine)

1.10 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₈H₅₅N₈O₂: 775.45; found 775.52; HRMS: Anal. Calcd. for [M + H]⁺C₅₀H₅₉N₈O₂: 775.4448; found 775.4456 23 N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))diformamide

1.22 minutes(Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₃N₈O₄: 747.34; found 747.38 24 1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediylcarbonyl))dicyc lopropanol

1.77 minutes(Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₄H₃₇N₆O₄: 593.29; found 593.16 24-1 1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))dipiperidine

¹HNMR(400 MHz, DMSO- d₆) δ 12.18(m, 0.4 H), 11.96 (m, 0.4 H), 11.79(m,1.2 H), 7.84-7.70(m, 4 H), 7.69-7.65 (m, 4 H), 7.53-7.50(m, 2 H),7.43-7.28(m, 4 H), 7.09-7.01 (m, 2 H), 6.87-6.85(m, 2 H), 5.51-5.48(m,0.5 H), 5.01- 4.98(m, 1.5 H), 4.29(m, 1.5 H), 4.16(m, 0.5 H), 3.98 (m, 2H), 3.65-3.49(m, 2 H), 3.43-3.36(m, 2 H), 2.41-2.31 (m, 8 H),2.14-1.82(m, 8 H), 1.47-1.31(m, 12 H); LCMS: Anal. Calcd. forC₅₂H₅₈N₈O₂: 826; found: 827(M + H)⁺. 24-2 1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))bis(4- methyl-4-piperidinol)

¹HNMR(400 MHz, DMSO- d₆) δ 12.02(br s, 1 H), 11.82 (br s, 1 H),7.90-7.79(m, 4 H), 7.79-7.65(m, 5 H), 7.55 (br s, 2 H), 7.45(d, J = 7.6Hz, 2 H), 7.39-7.25(m, 3 H), 7.34(d, J = 7.6 Hz, 2 H), 7.04(t, J = 7.6Hz, 2 H), 6.85(d, J = 8.1 Hz, 2 H), 5.15-4.96(m, 2 H), 4.31-3.96 (m, 6H), 2.35-2.20(m, 2 H), 2.05-1.94(m, 4 H), 1.94-1.81 (m, 4 H),1.50-1.35(m, 9 H), 1.35-1.20(m, 5 H), 1.09(s, 2 H), 1.05(s, 4 H); LCMS:Anal. Calcd. for C₅₄H₆₂N₈O₄: 886; found: 887(M + H)⁺. 24-3 dimethyl(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-1-(2- chlorophenyl)-2-oxo-2,1-ethanediyl)))biscarbamate

LCMS: Anal. Calcd. for C₄₆H₄₄Cl₂N₈O₆: 874; found: 875(M + H)⁺. 24-4aN′,N′′′-(4,4′- biphenyldiylbis(1H-imidazole- 4,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis(1,1-dimethylurea)

¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.89-2.00 (m, J = 17.09, 7.02 Hz, 4 H),2.06-2.13(m, J = 14.95, 3.97 Hz, 3 H), 2.24-2.33(m, J = 8.70, 6.56 Hz, 2H), 2.79- 2.84(m, 12 H), 3.29(q, 2 H), 3.95-4.03(m, 3 H), 5.26(dd, J =8.55, 2.14 Hz, 3 H), 5.52 (d, J = 5.80 Hz, 3 H), 6.72(d, J = 6.10 Hz, 3H), 7.02-7.07 (m, 1 H), 7.29-7.36(m, 3 H), 7.39(t, J = 7.17 Hz, 4 H),7.46(d, J = 7.02 Hz, 3 H), 7.92(s, 8 H), 8.12(s, 2 H); HPLC XTERRAC-184.6 × 30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90%water, 10% methanol, 0.2% H₃PO₄, B = 10% water, 90% methanol, 0.2%H₃PO₄, RT = 2.13 minutes, 96% homogeneity index; LCMS: Anal. Calcd. forC₄₈H₅₃N₁₀O₄: 832.42; found: 833.43(M + H)⁺; HRMS: Anal. Calcd. forC₄₈H₅₄N₁₀O₄ 833.4251; found: 833.4267(M + H)⁺. 24-4b N′,N′′′-(4,4′-biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))bis(1- methylurea)

RT = 4.45 minutes(Gemini C-184.6 × 50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mmammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammoniumacetate); LCMS: Anal. Calcd. for C₄₆H₄₈N₁₀O₄ 804.95; found: 805.41(M +H)⁺; HRMS: Anal. Calcd. for C₄₆H₄₉N₁₀O₄ 805.3938; found: 805.3929(M +H)⁺. 24-4c N′,N′′′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))bis(1- ethylurea)

RT = 4.20 minutes(Gemini C-184.6 × 50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mmammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammoniumacetate); LCMS: Anal. Calcd. for C₄₈H₅₂N₁₀O₄ 833.00; found: 833.48 (M +H)⁺. 24-4d N′,N′′′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))bis(1- cyclopentylurea)

RT = 4.92 minutes (Gemini C-184.6 × 50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 0 mmammonium acetate, B = 95%, acetonitrile, 5% water, 10 mm ammoniumacetate); LCMS: Anal. Calcd. for C₅₄H₆₀N₁₀O₄ 912.49; found: 913.68 (M +H)⁺; HRMS: Anal. Calcd. for C₅₄H₆₁N₁₀O₄ 913.4877; found: 913.4899 (M +H)⁺. 24-4e 2,2′-(4,4′-bipenyldiylbis(1H- imidaozle-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N-benzyl- N-methyl-2-oxoethanamine)

¹H NMR(500 MHz, DMSO- d₆) δ ppm 1.97-2.43(m, 8 H), 2.64-2.91(m, 6 H),3.45-3.63 (m, 2 H), 3.62-3.76(m, 2 H), 4.14(dd, 4 H), 4.22-4.45(m, 4 H),5.29(s, 2 H), 7.28-7.65 (m, 10 H), 7.90(s, 8 H), 8.06 (s, 2 H), 14.62(s,2 H); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minutehold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10%water, 90% methanol, 0.2% phosphoric acid. RT = 3.06 min; LCMS: Anal.Calcd. for: C₄₆H₅₀N₈O₂ 746.96; Found: 747.41 (M + H)⁺. 24-4f(2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N-benzyl- N-methyl-1-oxo-2- propanamine)

RT = 2.95 minutes (99%); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10minutes, one minute hold time, A = 90% water, 10% methanol, 0.2%phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid;LCMS: Anal. Calcd. for: C₄₈H₅₄N₈O₂ 775.02; Found: 775.45(M + H)⁺. 24-4g1,1′-(4,4′-biphenyldiylbis(1H- imidaozle-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N-benzyl- N,3-dimethyl-1-oxo-2- butanamine)

RT = 3.86 minutes(100%); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10minutes, one minute hold time, A = 90% water, 10% methanol, 0.2%phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid;LCMS: Anal. Calcd. for: C₅₂H₆₂N₈O₂ 831.13; Found: 831.51(M + H)⁺. 24-4h1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl(2-oxo-1- phenyl-2,1-ethanediyl)))di(4- piperidinol)

RT = 2.86 minutes(100%); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10minutes, one minute hold time, A = 90% water, 10% methanol, 0.2%phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid;LCMS: Anal. Calcd. for: C₅₂H₅₈N₈O₄ 859.09; Found: 859.45(M + H)⁺.

Examples 24-5 to 24-18

Example Compound Name Structure Data 24-5 1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2- diyl((2S,4S)-4- fluoro-2,1-pyrrolidinediyl)((1R)- 2-oxo-1- phenyl-2,1- ethanediyl))) dipiperidine

Gemini C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minutehold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B =95% acetonitrile, 5% water, 10 mm ammonium acetate. (RT = 4.163 min);Nominal/LRMS- Calcd. for C₄₆H₄₈F₂N₈O₂ 782.93; found 783.40 (M + H)⁺;Accurate/HRMS- Calcd. for C₄₆H₄₉F₂N₈O₂ 783.3946; 783.3934 (M + H)⁺. 24-6(1R,1′R)-2,2′- (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl((2S,4S)-4-fluoro-2,1- pyrrolidinediyl)))) bis(N,N-diethyl-2- oxo-1-phenylethanamine)

Gemini C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minutehold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B =95% acetonitrile, 5% water, 10 mm ammonium acetate. (RT = 3.76 min);LCMS: Anal. Calcd. for C₅₀H₅₆F₂N₈O₂ 839.04; found: 839.49 (M + H)⁺;HRMS: Anal. Calcd. for C₅₀H₅₇F₂N₈O₂ 839.4572; found: 839.4590 (M + H)⁺.24-7 (1R,1′R)-2,2′- (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl((2S,4S)-4- fluoro-2,1- pyrrolidinediyl)))) bis(N,N-dimethyl-2-oxo-1- phenylethanamine)

Gemini C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minutehold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B =95% acetonitrile, 5% water, 10 mm ammonium acetate. RT = 3.99 min; LCMS:Anal. Calcd. for C₅₂H₅₆F₂N₈O₂ 863.06; found: 863.47 (M + H)⁺; HRMS:Anal. Calcd. for C₅₂H₅₇F₂N₈O₂ 863.4572; found: 863.4553 (M + H)⁺. 24-81,1′-(4,4′- biphenyldiylbis(1H- imidazole-4,2- diyl((2S)-4,4-difluoro-2,1- pyrrolidinediyl)((1R)- 2-oxo-1- phenyl-2,1- ethanediyl)))dipiperidine

RT = 1.64 minutes, method B; LCMS: Anal. Calcd. for C₅₂H₅₄F₄N₈O₆:898.43; found: 899.46 (M + H)⁺; HRMS: Anal. Calcd. for C₅₂H₅₅F₄N₈O₆899.4384; found: 899.4380 (M + H)⁺. 24-9 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-4,2- diyl((2S)-4,4- difluoro-2,1-pyrrolidinediyl)((1R)- 2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate

RT = 2.62 minutes, method C; LCMS: Anal. Calcd. for C₄₆H₄₂F₄N₈O₆:878.88; found: 879.81 (M + H)⁺; HRMS: Anal. Calcd. for C₄₆H₄₃F₄N₈O₆879.33242; found: 879.3273 (M + H)⁺. 24-10 1-((1R)-2-((2S)-2-(4-(4′-(2-((2S)- 4,4-difluoro-1- ((2R)-2-phenyl-2- (1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazole-4- yl)-4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

RT = 1.54 minutes, method B; LCMS: Anal. Calcd. for C₅₂H₅₆F₂N₈O₆:862.45; found: 863.46 (M + H)⁺; HRMS: Anal. Calcd. for C₅₂H₅₇F₂N₈O₆863.4573; found: 863.4572 (M + H)⁺. 24-11 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-5,2- diyl((2S,4R)-4- hydroxy-2,1-pyrrolidinediyl)((1R)- 2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate

RT = 8.54 minutes, method A; LCMS: Anal. Calcd. for C₄₆H₄₆N₈O₈ 838.93;found: 839.41 (M + H)⁺; HRMS: Anal. Calcd. for C₄₆H₄₇N₈O₈ 839.9300;found: 839.3527 (M + H)⁺. 24-12 (3R,5S,3′R,5′S)- 5,5′-(4,4′-biphenyldiylbis(1H- imidazole-5,2- diyl))bis(1-((2R)- 2-hydroxy-2-phenylacetyl)-3- pyrrolidinol)

RT = 6.92 minutes, method A; LCMS: Anal. Calcd. for C₄₂H₄₀N₆O₆ 724.81;found: 725.43 (M + H)⁺; HRMS: Anal. Calcd. for C₄₂H₄₁N₆O₆ 725.3087;found: 725.3088 (M + H)⁺. 24-13 N,N″-(4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl((2S,4R)-4- hydroxy-2,1- pyrrolidinediyl)((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis(3- methylurea)

RT = 3.80 minutes, method C; LCMS: Anal. Calcd. for C₄₆H₄₈N₁₀O₆ 836.95;found: 837.52 (M + H)⁺; HRMS: Anal. Calcd. for C₄₆H₄₉N₁₀O₆ 837.3836;found: 837.3809 (M + H)⁺. 24-14 N′,N′′′-(4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl((2S,4R)-4- hydroxy-2,1- pyrrolidinediyl)((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis(1- ethylurea)

RT = 4.39 minutes, method C; LRMS: Anal. Calcd. for C₄₈H₅₂N₁₀O₆ 865.003;found: 865.56 (M + H)⁺; HRMS: Anal. Calcd. for C₄₈H₅₃N₁₀O₆ 865.4149;found: 865.4139 (M + H)⁺. 24-15 N′,N′′′-(4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl((2S,4R)-4- hydroxy-2,1- pyrrolidinediyl)((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis(1- cyclopentylurea)

RT = 4.88 minutes, method B; LRMS: Anal. Calcd. for C₅₄H₆₀N₁₀O₆ 944.13;found: 945.65 (M + H)⁺; HRMS: Anal. Calcd. for C₅₄H₆₁N₁₀O₆ 945.4775;found: 945.4769 (M + H)⁺. 24-16 (3S,5S,3′S,5′S)- 5,5′-(4,4′-biphenyldiylbis(1H- imidazole-5,2- diyl))bis(1-((2R)- 2-(dimethylamino)- 2-phenylacetyl)-3- pyrrolidinol)

RT = 3.66 minutes, method D; LRMS: Anal. Calcd. for C₄₆H₅₀N₈O₄ 778.39;found: 779.39 (M + H)⁺; HRMS: Anal. Calcd. for C₄₆H₅₁N₈O₄ 779.4033;found: 779.4021 (M + H)⁺. 24-17 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl((2S,4S)-4- hydroxy-2,1- pyrrolidinediyl)((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate

RT = 5.75 minutes, method C; LRMS: Anal. Calcd. for C₄₆H₄₆N₈O₈ 838.93;found: 839.44 (M + H)⁺; HRMS: Anal. Calcd. for C₄₆H₄₇N₈O₈ 839.3517;found: 839.3519 (M + H)⁺. 24-18 (3S,5S,3′S,5′S)- 5,5′-(4,4′-biphenyldiylbis(1H- imidazole-5,2- diyl))bis(1-((2R)- 2-hydroxy-2-phenylacetyl)-3- pyrrolidinol)

RT = 4.41 minutes, method D; LRMS: Anal. Calcd. for C₄₂H₄₀N₆O₆ 724.81;found: 725.13 (M + H)⁺. 24-18-1 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl((1S)-1,1- ethanediyl (methylimino) ((1R)-2-oxo-1-phenyl-2,1- ethanediyl))) biscarbamate

RT = 1.55 min¹; LRMS: Anal. Calcd. for C₄₄H₄₆N₈O₆ 782.35; found: 783.37(M + H)⁺; HRMS: Anal. Calcd. for C₄₄H₄₇N₈O₆ 783.3619 found: 783.3630(M + H)⁺. 24-18-2 (2R,2′R)-N,N′- (4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl(1S)-1,1- ethanediyl))bis(2- (dimethylamino)-N-methyl-2- phenylacetamide)

RT = 1.16 min¹; LRMS: Anal. Calcd. for C₄₄H₅₀N₈O₂ 722.41; found: 723.41(M + H)⁺; HRMS: Anal. Calcd. for C₄₄H₅₁N₈O₂ 723.4135 found: 723.4152(M + H)⁺. 24-18-3 (2R,2′R)-N,N′- (4,4′- biphenyldiylbis(1H-imidazole-5,2- diyl(1S)-1,1- ethandiyl))bis(N- methyl-2-phenyl- 2-(1-piperidinyl) acetamide)

RT = 1.28 min¹; LRMS: Anal. Calcd. for C₅₀H₅₈N₈O₂ 802.47; found: 803.50(M + H)⁺; HRMS: Anal. Calcd. for C₅₀H₅₉N₈O₂ 803.4761 found: 803.4778(M + H)⁺. 24-18-4 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((1S)-1-(((2R)-2-((methoxycarbonyl) amino)-2- phenylacetyl) methyl)amino)ethyl)-1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl) carbamate

RT = 1.53 min¹; LRMS: Anal. Calcd. for C₄₅H₄₆N₈O₆ 794.35; found: 795.39(M + H)⁺; HRMS: Anal. Calcd. for C₄₅H₄₇N₈O₆ 795.3619 found: 795.3616(M + H)⁺. 24-18-5 (2R)-2- (dimethylamino)- N-((1S)-1-(5-(4′-(2-((2S)-1-((2R)- 2- (dimethylamino)- 2-phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)ethyl)-N- methyl-2- phenylacetamide

RT = 1.21¹; LRMS: Anal. Calcd. for C₄₅H₅₀N₈O₂ 734.41; found: 735.46 (M +H)⁺; HRMS: Anal. Calcd. for C₄₅H₅₁N₈O₂ 735.4135 found: 735.4136 (M +H)⁺. 24-18-6 (2R)-N-methyl-2- phenyl-N-((1S)-1- (5-(4′-(2-((2S)-1-((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)ethyl)-2-(1-piperidinyl) acetamide

RT = 1.30¹; LRMS: Anal. Calcd. for C₅₁H₅₈N₈O₂ 814.47; found: 815.48 (M +H)⁺; HRMS: Anal. Calcd. for C₅₁H₅₉N₈O₂ 815.4761 found: 815.4744 (M +H)⁺. ¹LC Conditions for 24-18-1 through 24-18-6: Phenomenex LUNA C-184.6 × 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90%water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA,220 nm, 5 μL injection volume.

Examples 24-19 to 24-20

Example 24-19 and 24-20 were prepared as TFA salts from 1-2e-1 and therespective acids using the same method described for Example 1.

Example Compound Name

Data 24-19 methyl ((1R)-2-((2S)-2-(4- (3′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)- 2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.82-1.97 (m, 2 H), 1.97-2.17 (m, 4 H),2.18-2.37 (m, 2 H), 3.18 (d, J = 9.77 Hz, 2 H), 3.44-3.58 (m, 6 H),3.79-4.04 (m, 2 H), 5.09-5.46 (m, 2 H), 5.45-5.84 (m, 2 H), 6.97-7.49(m, 10 H), 7.61-7.74 (m, 4 H), 7.75-7.93 (m, 4 H), 8.10-8.32 (m, 4 H),14.48 (app br s, 2 H); RT = 1.34 min; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₄₇N₈O₆: 807.36; found 807.40 24-20 (1R)-2-((2S)-2-(4-(3′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-3-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.71-2.32 (m, 8 H), 3.33-3.68 (m, 2 H),3.89-4.16 (m, J = 2.75 Hz, 2 H), 4.96 (app br s, 12 H), 5.26 (s, 2 H),5.45 (s, 2 H), 7.03-7.78 (m, 12 H), 7.84 (s, 4 H), 8.07-8.43 (m, 4 H),9.90-10.87 (m, 2 H); RT = 1.10 min; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₅₁N₈O₂: 747.41; found 747.45LC conditions for 24-19 and 24-20:Column=Phenomenex-Luna 3.0×50 mm S10Start % B=0Final % B=100Gradient time=2 minStop time=3 minFlow Rate=4 mL/minWavelength=220 nmSolvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Examples 24-21 to 24-22

Example 24-21 and 24-22 were prepared as TFA salts from 1-4e and therespective carboxylic acids using the same method described for Example1.

Example Compound Name

Data 24-21 methyl ((1R)-2-((2R)-2-(4- (3′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)- 2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.73-2.37 (m, 8 H), 3.13 (s, 2 H),3.36-4.29 (m, 8 H), 5.26 (s, 2 H), 5.53 (s, 2 H), 6.99-8.61 (m, 22 H),14.51 (s, 2 H); RT = 1.33 min; LC/MS: Anal. Calcd. for [M +H]⁺C₄₆H₄₇N₈O₆: 807.36; found 807.58 24-22 (1R)-2-((2R)-2-(4-(3′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol- 4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.84-2.32 (m, 8 H), 2.92-3.10 (m, 2 H),3.92-4.08 (m, 2 H), 4.43 (app br s, 12 H), 5.16-5.37 (m, 2 H), 5.39-5.58(m, 2 H), 7.16-8.24 (m, 20 H), 9.60-10.46 (m, 2 H); RT = 1.08 min;LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₁N₈O₂: 747.41; found 747.45LC conditions for 24-21 and 24-22:Column=Phenomenex-Luna 3.0×50 mm S10Start % B=0Final % B=100Gradient time=2 minStop time=3 minFlow Rate=4 mL/minWavelength=220 nmSolvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Example 24-23

methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

A 50 mL flask equipped with a stir bar was sequentially charged with 2.5mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazolehydrate, 0.374 g (2.13 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine,0.400 g (2.09 mmol, 2.4 equiv)1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and anadditional 2.5 mL acetonitrile. The resulting solution was agitated at20° C. for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) ExampleA-1e-4. The slurry was cooled to about 0° C. and 0.45 g (3.48 mmol, 4equiv) diisopropylethylamine was added over 30 minutes while maintaininga temperature below 10° C. The solution was slowly heated to 15° C. over3 hours and held at 15° C. for 16 hours. The temperature was increasedto 20° C. and stirred for 3.25 hours. The resulting solution was chargedwith 3.3 g of 13 wt % aqueous NaCl and heated to 50° C. for 1 hour.After cooling to 20° C., 2.5 mL of isopropyl acetate was added. The richorganic phase was washed with 2×6.9 g of a 0.5 N NaOH solutioncontaining 13 wt % NaCl followed by 3.3 g of 13 wt % aqueous NaCl. Themixture was then solvent exchanged into isopropyl acetate by vacuumdistillation to a target volume of 10 mL. The resulting hazy solutionwas cooled to 20° C. and filtered through a 0.45 μm filter. The clearsolution was then solvent exchanged into ethanol by vacuum distillationwith a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 MHCl in ethanol was added. The mixture was then stirred at 25° C. for 15hours. The resulting slurry was filtered and the wet cake was washedwith 2.5 mL of 2:1 acetone:ethanol. The solids were dried in a vacuumoven at 50° C. to give 0.550 g (0.68 mmol, 77%) of the desired product.

Recrystallization of Example 24-23

A solution of Example 24-23 prepared above was prepared by dissolving0.520 g of the above product in 3.65 mL methanol. The solution was thencharged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed tostir for 0.25 hours. The mixture was then filtered and washed with 6 mlof methanol. The product rich solution was concentrated down to 2.6 mLby vacuum distillation. 7.8 mL acetone was added and allowed to stir at25° C. for 15 h. The solids were filtered, washed with 2.5 mL 2:1acetone:ethanol and dried in a vacuum oven at 70° C. to give 0.406 g(57.0%) of the desired product as white crystals: ¹H NMR (400 MHz,DMSO-d₆, 80° C.): 8.02 (d, J=8.34 Hz, 4H), 7.97 (s, 2H), 7.86 (d, J=8.34Hz, 4H), 6.75 (s, 2H), 5.27 (t, J=6.44 Hz, 2H), 4.17 (t, J=6.95 Hz, 2H),3.97-4.11 (m, 2H), 3.74-3.90 (m, 2H), 3.57 (s, 6H), 2.32-2.46 (m, 2H),2.09-2.31 (m, 6H), 1.91-2.07 (m, 2H), 0.88 (d, J=6.57 Hz, 6H), 0.79 (d,J=6.32 Hz, 6H); ¹³C NMR (75 MHz, DMSO-d₆): δ 170.9, 156.9, 149.3, 139.1,131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9,24.9, 19.6, 17.7; IR (neat, cm⁻¹): 3385, 2971, 2873, 2669, 1731, 1650.Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73.Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed).Characteristic diffraction peak positions (degrees 2θ±0.1)@RT, based ona high quality pattern collected with a diffractometer (CuKα) with aspinning capillary with 2θ calibrated with a NIST other suitablestandard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2,22.4, 22.7, 23.7.

Example 25N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))diacetamide

Example 25 Step a di-tert-butyl(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamateand Example 25 Step b

HATU (96.2 mg, 0.253 mmol) was added to a mixture of pyrrolidine 1e(52.6 mg, 0.124 mmol), diisopropylethylamine (100 μL, 0.57 mmol) andBoc-D-Phg-OH (69 mg, 0.275 mmol) in DMF (3.0 mL). The reaction mixturewas stirred for 25 minutes, and then diluted with methanol and purifiedby a reverse phase HPLC system (H₂O/methanol/TFA). The HPLC elute wasneutralized with excess 2.0 M/NH₃ in CH₃OH and the volatile componentwas removed in vacuo. The residue was carefully partitioned betweenCH₂Cl₂ and saturated NaHCO₃. The aqueous phase was extracted with moreCH₂Cl₂ (2×). The combined organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo to provide 25a as a film of semisolid oil (78.8mg). LC (Cond. 1): RT=1.99 min; >98% homogeneity index. LC/MS: Anal.Calcd. for [M+H]⁺ C₅₂H₅₉N₈O₆: 891.46. found 891.55.

Carbamate 25a was converted to amine 25b according to the proceduredescribed for the preparation of 1e. LC(Cond. 1): RT=1.44 min; 97%homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₄₃N₈O₂: 691.35.found 691.32

Example 25N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))diacetamide

Acetic anhydride (20 μL, 0.21 mmol) was added to a DMF (1.5 mL) solutionof amine 25b (29 mg, 0.042 mmol) and triethylamine (30 μL, 0.22 mmol)and stirred for 2.5 hours. The reaction mixture was then treated withNH₃/methanol (1 mL of 2 M) and stirred for an additional 1.5 hours. Thevolatile component was removed in vacuo and the residue was purified bya reverse phase HPLC system (H₂O/methanol/TFA) to provide the TFA saltof Example 25 as a white foam (28.1 mg). LC (Cond. 1): RT=1.61 min; >98%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₆H₄₇N₈O₄: 775.37.found 775.40; HRMS: Anal. Calcd. for [M+H]⁺ C₄₆H₄₇N₈O₄: 775.3720. found775.3723

Example 25-1 to 25-5

Examples 25-1 to 25-5 were prepared from 25b and the appropriatecarboxylic acid using standard amide forming conditions similar to thatdescribed for the preparation of example 1 from 1e. Examples 25-6 to25-8 were prepared from 25b and the appropriate carbamoyl chloride orisocyanate.

Example RT (LC-Cond.); % homogeneity Number Compound Name R index; MSdata 25-1 (2R,2′R)-N,N′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1-ethanediyl)))ditetrahydro-2- furancarboxamide

RT = 5.68 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₂H₅₄N₈O₆: 887.06; Found: 887.58 (M + H)⁺ 25-2 N,N′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis(1-methyl-1H-imidazole-5- carboxamide)

RT = 3.54 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₂H₅₀N₁₂O₄: 907.06; Found: 907.42 (M + H)⁺ 25-3(2S,2′S)-N,N′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis(1-methyl-2-pyrrolidinecarboxamide

RT = 3.1 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₄H₆₀N₁₀O₄ 913.14; Found: 913.54 (M + H)⁺ 25-4 N,N′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis(2-(3-pyridinyl)acetamide)

RT = 3.37 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₆H₅₂N₁₀O₄ 929.10 Found: 929.42 (M + H)⁺ 25-5 N,N′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis(2-dimethylamino)acetamide) (non-preferred name)

RT = 7.07 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₀H₅₆N₁₀O₄ 861.07 Found: 859.69 (M + H)⁺ 25-6 N,N′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))di(4-morpholinecarboxamide)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.86-2.18 (m, 6 H), 2.23-2.39 (m, 2 H),3.20-3.40 (m, 8 H), 3.40-3.61 (m, 8 H), 3.90-4.19 (m, 4 H), 5.27 (dd, J= 8.09, 3.51 Hz, 2 H), 5.37-5.63 (m, 2 H), 6.92-7.11 (m, 3 H), 7.30-7.45(m, 5 H), 7.44-7.56 (m, 4 H), 7.83-8.04 (m, 8 H), 8.15 (s, 2 H), 14.29(s, 2 H); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, oneminute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B =10% water, 90% methanol, 0.2% phosphoric acid, RT = 6.01 minutes; LCMS:Anal. Calcd. for: C₅₂H₅₆N₁₀O₆ 917.09; Found: 917.72 (M + H)⁺ 25-7N,N′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis(4-methyl-1-piperazinecarboxamide)

RT = 3.74 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₄H₆₂N₁₂O₄ 943.17; Found: 943.84 (M + H)⁺ 25-8 N,N″-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis(3-(3-pyridinyl)urea)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.79-2.17 (m, 6 H), 2.29 (d, J = 9.77Hz, 2 H), 3.06-3.39 (m, 2 H), 3.72-4.14 (m, 2 H), 5.27 (dd, J = 8.24,2.75 Hz, 2 H), 5.66 (d, J = 7.02 Hz, 2 H), 7.26-7.65 (m, 12 H),7.82-8.11 (m, 12 H), 8.17 (s, 2 H), 8.23-8.45 (m, 2 H), 8.61-8.97 (m, 2H), 9.38 (s, 2 H), 14.51 (s, 2 H); HPLC Xterra 4.6 × 50 mm, 0 to 100% Bover 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2%phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT =4.05 minutes; LCMS: Anal. Calcd. for: C₅₄H₅₀N₁₂O₄ 931.08; Found: 931.78(M + H)⁺.

Example 26 methyl((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example 26 Step a(2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(3-methyl-1-oxo-2-butanamine)

Diamine 26a was prepared starting from pyrrolidine 1e and BOC-D-Val-OHaccording to the procedure described for the synthesis of diamine 25b.

Example 26 methyl((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Methyl chloroformate (18 μL, 0.23 mmol) was added to a THF (1.5 mL)solution of diamine 26a (30 mg, 0.048 mmol) and triethylamine (30 μL,0.22 mmol), and the reaction mixture was stirred at ambient conditionfor 3 hours. The volatile components was removed in vacuo, and theresidue was treated with NH₃/methanol (2 mL of 2 M) and stirred atambient conditions for 15 minutes. All the volatile component wasremoved in vacuo, and the crude product was purified by reverse phaseprep-HPLC (H₂O/methanol/TFA) to provide the TFA salt of Example 26 as awhite solid (13.6 mg). LC (Cond. 2): RT=2.00 min; >98% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₀H₅₁N₈O₆: 739.39. found 739.67;HRMS: Anal. Calcd. for [M+H]⁺ C₄₀H₅₁N₈O₆: 739.3932. found 739.3966.

Example 27N-((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-acetamido-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)acetamide

Diamine 26a was converted to Example 27 (TFA salt) according to a methoddescribed in the preparation of Example 25. LC (Cond. 2): RT=1.93min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₀H₅₁N₈O₄:707.40. found 707.59; HRMS: Anal. Calcd. for [M+H]⁺ C₄₀H₅₁N₈O₄:707.4033. found 707.4054.

Example 28 methyl((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

Example 28 Step a

HATU (19.868 g, 52.25 mmol) was added to a heterogeneous mixture ofN-Cbz-L-proline (12.436 g, 49.89 mmol) and the HCl salt of2-amino-1-(4-bromophenyl)ethanone (12.157 g, 48.53 mmol) in DMF (156mL). The mixture was lowered in an ice-water bath, and immediatelyafterward N,N-diisopropylethylamine (27 mL, 155 mmol) was added dropwiseto it over 13 minutes. After the addition of the base was completed, thecooling bath was removed and the reaction mixture was stirred for anadditional 50 minutes. The volatile component was removed in vacuo;water (125 mL) was added to the resulting crude solid and stirred forabout 1 hour. The off-white solid was filtered and washed with copiouswater, and dried in vacuo to provide ketoamide 28a as a white solid(20.68 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 8.30 (m, 1H), 7.91(m, 2H), 7.75 (d, J=8.5, 2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H),4.57-4.48 (m, 2H), 4.33-4.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m,1H), 1.94-1.78 (m, 3H); LC (Cond. 1): RT=1.65 min; 98% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₁H₂₂BrN₂O₄: 445.08. found445.31.

Example 28 Step b

Ketoamide 28a (10.723 g, 24.08 mmol) was converted to 28b according tothe procedure described for the synthesis of carbamate 1b, with theexception that the crude material was purified by flash chromatography(sample was loaded with eluting solvent; 50% ethyl acetate/hexanes).Bromide 28b was retrieved as an off-white foam (7.622 g). ¹H NMR(DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.23/12.04/11.97 (m, 1H), 7.73-6.96(m, 10H), 5.11-4.85 (m, 3H), 3.61 (m, 1H), 3.45 (m, 1H), 2.33-184 (m,4H). LC (Cond. 1): RT=1.42 min; >95% homogeneity index; LC/MS: Anal.Calcd. for [M+H]⁺ C₂₁H₂₁BrN₃O₂: 426.08. found 426.31; HRMS: Anal. Calcd.for [M+H]⁺ C₂₁H₂₁BrN₃O₂: 426.0817. found: 426.0829. The optical purityof 28b was assessed using the following chiral HPLC methods, and an eeof 99% was observed.

Column: Chiralpak AD, 10 um, 4.6×50 mm

Solvent: 20% ethanol/heptane (isocratic)

Flow rate: 1 mL/min

Wavelength: 254 nm

Relative retention time: 1.82 minutes (R), 5.23 minutes (S)

Example 28 Step c benzyl tert-butyl(2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

Pd(Ph₃P)₄ (711.4 mg, 0.616 mmol) was added to a mixture of boronateester 1c (7.582 g, ˜17 mmol), bromide 28b (7.62 g, 17.87 mmol), NaHCO₃(4.779 g, 56.89 mmol) in 1,2-dimethoxyethane (144 mL) and water (48 mL).The reaction mixture was purged with N₂ and heated with an oil bath at80° C. for 15.5 hours, and then the volatile component was removed invacuo. The residue was partitioned between CH₂Cl₂ and water, and theaqueous layer was extracted with CH₂Cl₂. The combined organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultingmaterial was submitted to flash chromatography (sample was loaded as asilica gel mesh; ethyl acetate used as eluent) to provide biphenyl 28cas an off-white foam containing Ph₃PO impurity (7.5 g). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 400 MHz): δ 12.24-12.19 (m, 0.36H), 12.00-11.82 (m, 1.64H),7.85-6.98 (15H), 5.12-4.74 (4H), 3.68-3.34 (4H), 2.34-1.79 (8H),1.41/1.17 (two br S, 9H); LC (Cond. 1): RT=1.41 minutes; LC/MS: Anal.Calcd. for [M+H]⁺ C₃₉H₄₃N₆O₄: 659.34. found 659.52; HRMS: Anal. Calcd.for [M+H]⁺ C₃₉H₄₃N₆O₄: 659.3346. found 659.3374.

Example 28 Step d tert-butyl(2S)-2-(5-(4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

K₂CO₃ (187.8 mg, 1.36 mmol) was added to a mixture of catalyst (10%Pd/C, 205.3 mg), carbamate 28c (1.018 g, ˜1.5 mmol), methanol (20 mL)and 3 pipet-drops of water. A balloon of H₂ was attached and the mixturewas stirred for 6 hours. Then, additional catalyst (10% Pd/C, 100.8 mg)and K₂CO₃ (101.8 mg, 0.738 mmol) were added and stirring continued for3.5 hours. During the hydrogenation process, the balloon of H₂ waschanged at intervals three times. The reaction mixture was filteredthrough a pad of diatomaceous earth (Celite® 521), and the filterate wasremoved in vacuo. The resulting crude material was submitted to flashchromatography using a short column (sample was loaded as a silica gelmesh; 0-20% methanol/CH₂Cl₂ used as eluent) to provide 28d as alight-yellow foam (605.6 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ12.18/11.89/11.82 (three br s, 2H), 7.83-7.29 (m, 10H), 4.89-4.73 (m,1H), 4.19 (app t, J=7.2, 1H), 3.55 (app br s, 1H), 3.40-3.35 (m, 1H),3.02-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-1.69 (m, 8H), 1.41/1.16 (twobr s, 9H). Note: the signal of pyrrolidine NH appears to have overlappedwith signals in the 3.6-3.2 ppm region; LC (Cond. 1): RT=1.21 min; >95%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₁H₃₇N₆O₂: 525.30.found 525.40.

Example 28 Step e-f Example 28 Step e tert-butyl(2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylateExample 28 Step f methyl((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

Step e: HATU (316.6 mg, 0.833 mmol) was added to a DMF (7.0 mL) solutionof pyrrolidine 28d (427 mg, 0.813 mmol), Cap-4 (177.6 mg, 0.849 mmol)and diisopropylethylamine (0.32 mL, 1.84 mmol), and the reaction mixturewas stirred for 45 minutes. The volatile component was removed in vacuo,and the residue was partitioned between CH₂Cl₂ (50 mL) and an aqueousmedium (20 mL H₂O+1 mL saturated NaHCO₃ solution). The aqueous phase wasre-extracted with CH₂Cl₂, and the combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo. The resulting yellow oilwas purified by flash chromatography (silica gel; ethyl acetate) toprovide 28e as a yellow foam (336 mg). LC (Cond. 1): RT=1.68 min; 91%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₁H₄₆N₇O₅: 716.35.found 716.53.

Step f: Carbamate 28e was elaborated to amine 28f by employing theprocedure described in the conversion of 1d to 1e. LC (Cond. 1): RT=1.49min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₃₆H₃₈N₇O₃:616.30. found 616.37; HRMS: Anal. Calcd. for [M+H]⁺ C₃₆H₃₈N₇O₃:616.3036. found 616.3046.

Example 28 methyl((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

Amine 28f was converted to the TFA salt of Example 28 by employing thelast step of the synthesis of Example 1. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400MHz): δ 8.21-7.03 (m, 21H), 5.78-5.14 (3H), 3.98-3.13 (m, 9H; includesthe signal for OCH₃ at 3.54 & 3.53), 2.45-1.72 (m, 8H). LC (Cond. 1):RT=1.66 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₄H₄₄N₇O₄: 734.35. found 734.48; HRMS: Anal. Calcd. for [M+H]⁺C₄₄H₄₄N₇O₄: 734.3455; 734.3455.

Example 28-1 to 28-4

Examples 28-1 through 28-4 (R groups shown in the table below) wereprepared in similar fashion to example 28 via the intermediacy ofintermediate 28d.

Example 28-1(1R)—N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

Cap-1 was appended, the Boc carbamate was removed with TFA or HCl, andCap-14 was appended.

Example 28-21-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)piperidine

Tetrahydrofuroic acid was appended, the Boc carbamate was removed withTFA or HCl, and Cap-14 was appended.

Example 28-3 methyl((1R)-1-(2-chlorophenyl)-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

Cap-40 was appended, the Boc carbamate was removed with TFA or HCl, andCap-14 was appended.

Example 28-4(1R)-1-(2-chlorophenyl)-N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

Cap-39 was appended, the Boc carbamate was removed with TFA or HCl, andCap-14 was appended.

Example 28-5(1R)-1-(2-fluorophenyl)-N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

Cap-38 was appended, the Boc carbamate was removed with TFA or HCl, andCap-14 was appended.

Example Compound Name R Data 28-1 (1R)-N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₉H₅₄N₈O₂: 786; found: 787 (M +H)⁺. 28-21-((1R)-2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)piperidine

LCMS: Anal. Calcd. for C₄₄H₄₉N₇O₃: 723; found: 724 (M +H)⁺. 28-3 methyl((1R)-1-(2- chlorophenyl)-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₉H₅₁ClN₈O₄: 850; found: 851 (M +H)⁺. 28-4(1R)-1-(2-chlorophenyl)- N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₉H₅₃ClN₈O₂: 820; found: 821 (M +H)⁺. 28-5(1R)-1-(2-fluorophenyl)- N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₉H₅₃FN₈O₂: 804; found: 805 (M +H)⁺.

Example 29 methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4-methyl-1-piperazinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

4-Methylpiperazine-1-carbonyl chloride/HCl (11.6 mg, 0.58 mmol) wasadded to a mixture of 28f (30 mg, 0.049 mmol), triethylamine (15 μl,0.11 mmol) and THF (1.0 mL), and stirred at ambient conditions for 1hour. The volatile component was removed in vacuo, and the residue waspurified by a reverse phase HPLC (H₂O/methanol/TFA) to provide the TFAsalt of Example 29 as a light yellow foam (29.3 mg). LC (Cond. 2):RT=1.82 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₂H₄₈N₉O₄: 742.38. found 742.49.

Example 30 methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-glycyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Example 30 Step a methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(tert-butoxycarbonyl)glycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Carbamate 30a was prepared from pyrrolidine 28f and Boc-Glycine by usingthe procedure described for the preparation of 25a from 1e. LC (Cond.2): RT=2.12 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺ C₄₃H₄₉N₈O₆: 773.38. found 773.46

Example 30 methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-glycyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Carbamate 30a was converted to Example 30 according to the proceduredescribed for the preparation of 1e from 1d. LC (Cond. 2): RT=1.81minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₃₈H₄₁N₈O₄: 673.33. found 673.43

HRMS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₁N₈O₄: 673.3251. found 673.3262

Example 30-1 methyl((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-j-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

Example 30-1 was prepared in three steps from Example 28d. Step one:Append Cap-2 using the procedure describing the synthesis of 28e from28d. Step two: Hydrolyze the Boc carbamate using the proceduredescribing the synthesis of 28f from 28e. Step three: Append Cap-52using the procedure describing the synthesis of 28e from 28d. RT=1.70min (Cond. 1b); >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺C₄₃H₅₁N₈O₄: 743.40. found, 743.50. HRMS: Anal. Calcd. for [M+H]⁺C₄₃H₅₁N₈O₄: 743.4033. found, 743.4053

Substituting the appropriate acid chloride or carboxylic acid intoExample 29 or 30, the following compounds (Example 31 to 84-87) wereprepared as TFA salts.

Example 31 to 84-88

Example Compound Name

Retention time (LC-Condition); homogeneity index MS data 31 methyl((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-acetyl-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.54 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₀N₇O₄: 658.31; found 658.42; HRMS: Anal. Calcd. for [M + H]⁺C₃₈H₄₀N₇O₄: 658.3142; found 658.3135 32 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- propionyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.57 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₉H₄₂N₇O₄: 672.33; found 672.46; HRMS: Anal. Calcd. for [M + H]⁺C₃₉H₄₂N₇O₄: 672.3298; found 672.3299 33 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (cyclopropylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.59 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₂N₇O₄: 684.33; found 684.44; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₂N₇O₄: 684.3298; found 684.3324 34 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (cyclopropylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.61 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₂N₇O₄: 698.35; found 698.48; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₂N₇O₄: 698.3455; found 698.3489 35 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- hydroxypropanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.54 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₉H₄₂N₇O₅: 688.33; found 688.47 36 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.59 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄N₇O₅: 714.34; found 714.49; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄N₇O₅: 714.3404; found 714.3430 37 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N- dimethylglycyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.48 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₅N₈O₄: 701.36; found 701.49; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₅N₈O₄: 701.3564; found 701.3553 38 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.20 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₄₉N₈O₄: 777.39; found 777.61; HRMS: Anal. Calcd. for [M + H]⁺C₄₆H₄₉N₈O₄: 777.3877; found 777.3909 39 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(4- morpholinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.79 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₅: 743.37; found 743.49; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₅: 743.3669; found 743.3672 40 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)carbamate

1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₃N₈O₆: 731.33; found 731.42; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₃N₈O₆: 731.3306; found 731.3333 41 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-acetylglycyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.86 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₃N₈O₅: 715.34; found 715.49; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₃N₈O₅: 715.3356; found 715.3369 42 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.85 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₄₉N₈O₄: 777.39; found 777.56 43 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-hydroxy-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.96 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₄N₇O₅: 750.34; found 750.51; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₄₄N₇O₅: 750.3404; found 750.3437 44 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((1-methyl-4- piperidinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.78 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₉N₈O₄: 741.39; found 741.55; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₄₉N₈O₄: 741.3877; found 741.3893 45 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (tetrahydro-2H-pyran-4-ylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)ethyl)carbamate

1.87 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₇O₅: 728.36; found 728.52; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₇O₅: 728.3560; found 728.3587 46 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- pyridinylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₈O₄: 735.34; found 735.51; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₈O₄: 735.3407; found 735.3416 47 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3- pyridinylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.76 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₈O₄: 735.34; found 735.52 48 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(4- pyridinylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₈O₄: 735.34; found 735.50; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₈O₄: 735.3407; found 735.3405 49 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((1-methyl-1H- imidazol-5-yl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₂N₉O₄: 724.34; found 724.51; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₂N₉O₄: 724.3360; found 724.3380 50 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (dimethylcarbamoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₉H₄₃N₈O₄: 687.34; found 687.49; HRMS: Anal. Calcd. for [M + H]⁺C₃₉H₄₃N₈O₄: 687.3407; found 687.3414 51 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1-methyl-D- prolyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.79 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₄: 727.37; found 727.34; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₄: 727.3720; found 727.3719 52 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1-methyl-L- prolyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₄: 727.37; found 727.33; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₄: 727.3720; found 727.3738 53 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-acetyl-D- alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₅: 729.35; found 729.33; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₅: 729.3513; found 729.3530 54 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-acetyl-L- alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.87 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₅: 729.35; found 729.33 55 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(methoxyacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.89 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₉H₄₂N₇O₅: 688.32; found 688.28; HRMS: Anal. Calcd. for [M + H]⁺C₃₉H₄₂N₇O₅: 688.3247; found 688.3231 56 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- hydroxybutanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₄N₇O₅: 702.34; found 702.30; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₄N₇O₅: 702.3404; found 702.3393 57 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4-methyl-1- piperazinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₅₀N₉O₄: 756.40; found 756.36; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₅₀N₉O₄: 756.3986; found 756.3965 58 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(1- pyrrolidinylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.82 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₄: 727.37; found 727.33; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₄: 727.3720; found 727.3696 59 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.94 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₃N₇O₅: 714.34; found 714.24 60 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((1- hydroxycyclopropyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.93 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₂N₇O₅: 700.32; found 700.23; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₂N₇O₅: 700.3247; found 700.3265 61 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1H-imidazol-5- ylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₂N₉O₄: 724.34; found 724.21; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₂N₉O₄: 724.3360; found 724.3365 62 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((1-methyl-1H- imidazol-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.85 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₄N₉O₄: 738.35; found 738.22; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₄N₉O₄: 738.3516; found 738.3539 63 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1H-imidazol-2- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.95 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₁N₉O₄: 710.32; found 710.17 64 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4-hydroxy-1- piperidinyl)(phenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₉H₅₃N₈O₅: 833.41; found 833.32; HRMS: Anal. Calcd. for [M + H]⁺C₄₉H₅₃N₈O₅: 833.4139; found 833.4163 65 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-tetrazol-5-ylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₉H₄₀N₁₁O₄: 726.33; found 726.22; HRMS: Anal. Calcd. for [M + H]⁺C₃₉H₄₀N₁₁O₄: 726.3265; found 726.3290 67 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- pyridinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

2.03 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₈O₄: 721.33; found 721.31; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₈O₄: 721.3251; found 721.3247 68 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3- pyridinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₈O₄: 721.33; found 721.31; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₈O₄: 721.3251; found 721.3226 69 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-isonicotinoyl-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.89 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₈O₄: 721.33; found 721.29; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₁N₈O₄: 721.3251; found 721.3251 70 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4R)-4-fluoro-1- methyl-L-prolyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆FN₈O₄: 745.36; found 745.27; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆FN₈O₄: 745.3626; found 745.3658 71 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-oxazol-2- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.97 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₃₉N₈O₅: 711.30; found 711.27 72 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-oxazol-5- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.95 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₃₉N₈O₅: 711.30; found 711.27; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₃₉N₈O₅: 711.3043; found 711.3078 73 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(oxo)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₃N₈O₅: 715.34; found 715.40 74 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (tetrahydro-3- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄N₇O₅: 714.34; found 714.39; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄N₇O₅: 714.3404; found 714.3433 75 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.94 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₆: 745.35 found 745.34; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₆: 745.3462; found 745.3486 76 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dimethyl- L-alanyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₄: 715.37; found 715.35; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₄: 715.3720; found 715.3737 77 methyl (2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

1.97 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₀N₇O₅: 674.31; found 674.66; HRMS: Anal. Calcd. for [M + H]⁺C₃₈H₄₀N₇O₅: 674.3091; found 674.3110 78 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(4- morpholinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.95 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₅: 729.35; found 729.40; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₅: 729.3513; found 729.3502 79 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4S)-4-fluoro-L- prolyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄FN₈O₄: 731.84; found 731.26 80 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-L- prolyl-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)carbamate

1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₄: 713.36; found 713.36; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₅N₈O₄: 713.3564; found 713.3563 81 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(4,4-difluoro-L- prolyl-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.88 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₃F₂N₈O₄: 749.34; found 749.31; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₃F₂N₈O₄: 749.3375; found 749.3390 82 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4R)-4-fluoro-L- prolyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.83 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄FN₈O₄: 731.35; found 731.37; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄FN₈O₄: 731.3470; found 731.3502 83 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((1S,3S,5S)-2- azabicyclo[3.1.0]hex-3- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.82 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₅N₈O₄: 725.36; found 725.39; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₅N₈O₄: 725.3564; found 725.3574 84 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-L-alanyl-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.82 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₉H₄₃N₈O₄: 687.34; found 687.32; HRMS: Anal. Calcd. for [M + H]⁺C₃₉H₄₃N₈O₄: 687.3407; found 687.3435 84-1 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate

¹HNMR (400 MHz, CD₃OD) δ 7.90-7.85 (m, 9 H), 7.81-7.79 (m, 1 H),7.63-7.57 (m, 5 H), 7.45-7.32 (m, 6 H), 5.51 (s, 1 H), 5.45 (s, 1 H),5.33-5.29 (m, 2 H), 4.06-4.01 (m, 2 H), 3.63 (d, J = 4.04 Hz, 3 H),3.59-3.50 (m, 2 H), 3.19-3.12 (m, 1 H), 3.07-3.01 (m, 1 H), 2.93-2.76(m, 2 H), 2.57-2.51 (m, 1 H), 2.40-2.31 (m, 2 H), 2.22-2.06 (m, 4 H),2.00-1.90 (m, 3 H), 1.84-1.64 (m, 4 H), 1.52-1.43 (m, 2 H); LCMS: Anal.Calcd. for C₄₉H₅₂N₈O₄: 816; found: 817 (M + H)⁺. 84-2 methyl((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)-2-(2- fluorophenyl)-2-hydroxypropanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

¹HNMR (400 MHz, CD₃OD) δ 7.89-7.85 (m, 8 H), 7.81-7.73 (2 H), 7.67-7.65(m, 1 H), 7.45-7.26 (m, 7H), 7.13-7.08 (m, 1 H), 6.94-6.89 (m, 0.5 H),6.72-6.67 (0.5 H), 6.09-6.07 (m, 0.4 H), 5.51 (s, 1 H), 5.32-5.25 (m,1.6 H), 4.08-3.95 (m, 2 H), 3.85-3.79 (1 H), 3.64-3.63 (m, 3 H),3.56-3.49 (1 H), 3.09-3.03 (m, 1 H), 2.59-2.50 (m, 1 H), 2.42-2.33 (m, 2H), 2.21-2.00 (m, 6 H), 1.82-1.74 (m, 1 H), 1.66 (d, J = 4.55 Hz, 3 H);LCMS: Anal. Calcd. for C₄₅H₄₆FN₇O₃: 781; found: 782 (M + H)⁺. 84-3methyl ((1R)-2-oxo-2-((2S)-2- (5-(4′-(2-((2S)-1-(5-oxo-D-prolyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₁H₄₂N₈O₅: 726; found: 727 (M + H)⁺. 84-4 methyl((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-(4- hydroxy-4-methyl-1-piperidinyl)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₅₄N₈O₅: 846; found: 847 (M + H)⁺. 84-5tert-butyl (4R)-4-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 1,3-thiazolidine-3-carboxylate

LCMS: Anal. Calcd. for C₄₅H₅₀N₈O₆S: 830; found: 831 (M + H)⁺. 84-6methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((1-((tert-butoxycarbonyl)amino) cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₅₄FN₈O₆: 826; found: 827 (M + H)⁺. 84-7methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N-benzoylglycyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₄FN₈O₅: 776; found: 777 (M + H)⁺. 84-8methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(4-(4-methyl-1-piperazinyl)benzoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₁N₉O₄: 817; found: 818 (M + H)⁺. 84-9 methyl((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((5-phenyl-2-thienyl)carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₄₃N₇O₄S: 801; found: 802 (M + H)⁺. 84-10methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((4-phenyl-1,2,3-thiadiazol-5- yl)carbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₁N₉O₄S: 803; found: 804 (M + H)⁺. 84-11methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2-phenyl-1,3-thiazol-4- yl)carbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₂N₈O₄S: 802; found: 803 (M + H)⁺. 84-12tert-butyl 4-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 4-methyl-1- piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₈H₅₆N₈O₆: 840; found: 841 (M + H)⁺. 84-13methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(4-(dimethylamino)butanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₄₈N₈O₄: 728; found: 729 (M + H)⁺. 84-14methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((3- hydroxyphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₃N₇O₅: 749; found: 750 (M + H)⁺. 84-15methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N,N-dimethyl-beta-alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₁H₄₆N₈O₄: 714; found: 715 (M + H)⁺. 84-16methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(4- (hydroxymethyl)benzoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₃N₇O₅: 749; found: 750 (M + H)⁺. 84-17methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(((3R)-1-benzyl-3-pyrrolidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₄: 802; found: 803 (M + H)⁺. 84-18tert-butyl (2S)-2-(2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxoethyl)-1- pyrrolidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₄N₈O₆: 826; found: 827 (M + H)⁺. 84-19methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((5-methyl-1H-pyrazol-3-yl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₄₃N₉O₄: 737; found: 738 (M + H)⁺. 84-20methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(((3S)-7-hydroxy-1,2,3,4-tetrahydro-3- isoquinolinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₆N₈O₅: 790; found: 791 (M + H)⁺. 84-21tert-butyl (2R)-2-(2-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1- piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₄N₈O₆: 826; found: 827 (M + H)⁺. 84-22methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((5-phenyl-4-isoxazolyl)carbonyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₂N₈O₅: 786; found: 787 (M + H)⁺. 84-23methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(((1R,3S)-3-((tert-butoxycarbonyl)amino) cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₅₄N₈O₆: 826; found: 827 (M + H)⁺. 84-24methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(3-(1-piperidinyl)propanoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₅₀N₈O₄: 754; found: 755 (M + H)⁺. 84-25methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(2- benzoylbenzoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₄₅N₇O₅: 823; found: 824 (M + H)⁺. 84-26methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2- methoxyphenoxy)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₆: 779; found: 780 (M + H)⁺. 84-27tert-butyl 3-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1- azetidinecarboxylate

LCMS: Anal. Calcd. for C₄₅H₅₀N₈O₆: 798; found: 799 (M + H)⁺. 84-28methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(((3S)-1-benzyl-3-pyrrolidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₄: 802; found: 803 (M + H)⁺. 84-29methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(3-(1-pyrrolidinyl)benzoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₄₈N₈O₄: 788; found: 789 (M + H)⁺. 84-30methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(2-((tert-butoxycarbonyl)amino)benzoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₆: 834; found: 835 (M + H)⁺. 84-31tert-butyl (3R)-3-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1- piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₄N₈O₆: 826; found: 827 (M + H)⁺. 84-32methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((1-trifluoromethyl)cyclopropyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₁H₄₀F₃N₇O₄: 751; found: 752 (M + H)⁺. 84-33methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(4- (dimethylamino)benzoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₆N₈O₄: 762; found: 763 (M + H)⁺. 84-34methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(3- benzoylbenzoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₄₅N₇O₅: 823; found: 824 (M + H)⁺. 84-35methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((cis-4-((tert-butoxycarbonyl)amino) cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₆N₈O₆: 840; found: 841 (M + H)⁺. 84-36tert-butyl 4-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1- piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₄N₈O₆: 826; found: 827 (M + H)⁺. 84-37methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((cis-4-((tert-butoxycarbonyl)amino) cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₆N₈O₆: 840; found: 841 (M + H)⁺. 84-38methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(diphenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₄₇N₇O₄: 809; found: 810 (M + H)⁺. 84-39methyl ((1R)-2-oxo-2-((2S)-2- (5-(4′-(2-((2S)-1-(4-oxopentanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₁H₄₃N₇O₅: 713; found: 714 (M + H)⁺. 84-40methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(2-fluorobenzoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₃H₄₀FN₇O₄: 737; found: 738 (M + H)⁺. 84-41methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(2- biphenylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₉H₄₅N₇O₄: 795; found: 796 (M + H)⁺. 84-42methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(2-benzylbenzoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₄₇N₇O₄: 809; found: 810 (M + H)⁺. 84-43methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2E)-3-(4-(dimethylamino)phenyl)-2- propenoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₄₈N₈O₄: 788; found: 789 (M + H)⁺. 84-44methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-thiazol-4-ylcarbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₀H₃₈N₈O₄S: 726; found: 727 (M + H)⁺. 84-45methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((((1R,2S,5R)-2- isopropyl-5-methylcyclohexyl)oxy)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₇N₇O₅: 811; found: 812 (M + H)⁺. 84-46methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(2-thienyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₆N₈O₄S: 782; found: 782 (M + H)⁺. 84-47methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(3-thienyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₆N₈O₄S: 782; found: 782 (M + H)⁺. 84-48methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(2-methyl-1,3-thiazol-4-yl)acetyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₇N₉O₄S: 797; found: 798 (M + H)⁺. 84-49methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(1,2-benzisoxazol-3-yl(dimethylamino)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₄₇N₉O₅: 817; found: 818 (M + H)⁺. 84-50methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(1-benzothiophen-3-yl(dimethylamino)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₄₈N₈O₄S: 832; found: 833 (M + H)⁺. 84-51methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(1-naphthyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₅₀N₈O₄: 826; found: 827 (M + H)⁺. 84-52methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(3-quinolinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₉H₄₉N₉O₄: 827; found: 828 (M + H)⁺. 84-53methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(2-methyl-1,3-benzothiazol-5-yl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₄₉N₉O₄S: 847; found: 848 (M + H)⁺. 84-54methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(3-(trifluoromethyl)phenyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₄₇F₃N₈O₄: 844; found: 845 (M + H)⁺. 84-55methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(2-(trifluoromethyl)phenyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₄₇F₃N₈O₄: 844; found: 845 (M + H)⁺. 84-56methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2-chlorophenyl)(dimethylamino) acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇ClN₈O₄: 810; found: 811 (M + H)⁺. 84-57methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((3-chlorophenyl)(dimethylamino) acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇ClN₈O₄: 810; found: 811 (M + H)⁺. 84-58methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((4-chlorophenyl)(dimethylamino) acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇ClN₈O₄: 810; found: 811 (M + H)⁺. 84-59methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(2-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇FN₈O₄: 794; found: 795 (M + H)⁺. 84-60methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(3-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇FN₈O₄: 794; found: 795 (M + H)⁺. 84-61methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(2-pyridinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₇N₉O₄: 777; found: 778 (M + H)⁺. 84-62methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((dimethylamino)(3-pyridinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₇N₉O₄: 777; found: 778 (M + H)⁺. 84-63methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((4- methoxyphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₅: 763; found: 764 (M + H)⁺. 84-64methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((3- methoxyphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₅: 763; found: 764 (M + H)⁺. 84-65methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2- methoxyphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₅: 763; found: 764 (M + H)⁺. 84-66methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2- chlorophenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₂ClN₇O₄: 767; found: 768 (M + H)⁺. 84-67methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((3- chlorophenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₂ClN₇O₄: 767; found: 768 (M + H)⁺. 84-68methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((4- chlorophenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₂ClN₇O₄: 767; found: 768 (M + H)⁺. 84-69methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2- methylphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₄: 747; found: 748 (M + H)⁺. 84-70methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((4- methylphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₄: 747; found: 748 (M + H)⁺. 84-71methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((3- methylphenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₄: 747; found: 748 (M + H)⁺. 84-72methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2-methyl-1,3-thiazol-4-yl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₄₂N₈O₄S: 754; found: 755 (M + H)⁺. 84-73methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(3-thienylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₄₁N₇O₄S: 739; found: 740 (M + H)⁺. 84-74methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((3-methyl-5-isoxazolyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₄₂N₈O₅: 738; found: 739 (M + H)⁺. 84-75methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(cyclohexylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₄₉N₇O₄: 739; found: 740 (M + H)⁺. 84-76methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenylpropanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₄: 747; found: 748 (M + H)⁺. 84-77methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((1-phenylcyclopropyl)carbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₅N₇O₄: 759; found: 760 (M + H)⁺. 84-78methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((1-(4-chlorophenyl)cyclopropyl) carbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₄ClN₇O₄: 793; found: 794 (M + H)⁺. 84-79methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(2-(4- chlorophenyl)-2-methylpropanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₆ClN₇O₄: 795; found: 796 (M + H)⁺. 84-80methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-methoxy-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₅N₇O₅: 763; found: 764 (M + H)⁺. 84-81methyl ((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3,3,3-trifluoro-2- methoxy-2-phenylpropanoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₄F₃N₇O₅: 831; found: 832 (M + H)⁺. 84-82(1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1- phenylethylacetate

LCMS: Anal. Calcd. for C₄₆H₄₅N₇O₆: 791; found: 792 (M + H)⁺. 84-83(1S)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1- phenylethylacetate

LCMS: Anal. Calcd. for C₄₆H₄₅N₇O₆: 791; found: 792 (M + H)⁺. 84-84methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2-(4-morpholinylmethyl)phenyl) acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₉H₅₂N₈O₅: 832; found: 833 (M + H)⁺. 84-85methyl ((1R)-2-oxo-1-phenyl- (2-((2S-2-(5-(4′-(2-((2S)-1-((2-(1-piperidinylmethyl)phenyl) acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₅₄N₈O₄: 830; found: 831 (M + H)⁺. 84-86methyl ((1R)-2-oxo-1-phenyl- (2-((2S-2-(5-(4′-(2-((2S)-1-((2-(1-pyrrolidinylmethyl)phenyl) acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₉H₅₂N₈O₄: 816; found: 816 (M + H)⁺. 84-87methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2-((dimethylamino)methyl)phenyl) acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₅₀N₈O₄: 790; found: 791 (M + H)⁺.

Examples 85-94

      Example       Compound Name

Retention time (LC- Condition); homogeneity index MS data 85(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3-pyridinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

1.64 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₅N₈O₂: 705.37; found 705.43; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₄₅N₈O₂: 705.3665; found 705.3675 86 (1R)-N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

1.73 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₆N₇O₃: 684.37; found 684.44; HRMS Anal. Calcd. for [M + H]⁺C₄₁H₄₆N₇O₃: 684.3662; found 684.3671 87 (1R)-N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2S)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

1.12 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₆N₇O₃: 684.37; found 684.68; HRMS Anal. Calcd. for [M + H]⁺C₄₁H₄₆N₇O₃: 684.3662; found 684.3692 88 (1R)-N,N-dimethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((1-methyl-1H- imidazol-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethanamine

1.66 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₉O₂: 708.38; found 708.36 89 (1R)-N,N-dimethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(4- morpholinyl)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethanamine

1.70 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₅N₈O₄: 701.36; found 701.34; HRMS: Anal. Calcd. for [M + H]⁺C₄₀H₄₅N₈O₄: 701.3564; found 701.3576 90 (1R)-N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-phenyl-2-(1-pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₈H₅₃N₈O₂: 773.43; found 773.42; HRMS: Anal. Calcd. for [M + H]⁺C₄₈H₅₃N₆O₂: 773.4291; found 773.4309 91 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxoethyl)carbamate

1.66 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₉O₂: 708.38; found 708.36; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₉O₂: 708.3774; found 708.3770 92 methyl((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

1.73 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₄: 715.37; found 715.41; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₄: 715.3720; found 715.3729 93 (1R)-N,N-dimethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(4- morpholinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethanamine

1.76 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₃: 699.38; found 699.45; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₃: 699.3771; found 699.3803 94 (1R)-N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-(1-pyrrolidinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

1.86 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₂: 683.38; found 683.46; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₇N₈O₂: 683.3822; found 683.3835 94-1(2S)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-(2-fluorophenyl)-1-oxo-2-propanol

¹HNMR (400 MHz, CD₃OD) δ 7.90-7.84 (m, 9 H), 7.79-7.73 (m, 2 H),7.67-7.65 (m, 1 H), 7.63-7.52 (m, 5 H), 7.39-7.36 (m, 1 H), 7.30-7.26(m, 1 H), 7.13-7.08 (m, 1 H), 6.93-6.88 (m, 0.5 H), 6.72-6.67 (m, 0.5H), 5.51 (s, 0.2 H), 5.46 (s, 0.8 H), 5.33-5.30 (m, 1 H), 5.28-5.24 (m,1 H), 4.05-3.94 (m, 2 H), 3.84-3.73 (m, 1 H), 3.69-3.55 (m, 1 H),3.21-3.04 (m, 2 H), 2.79 (br s, 6 H), 2.39- 2.33 (m, 2 H), 2.21- 1.93(m, 5 H),1.65 (d, J = 4.55 Hz, 3 H).; LCMS: Anal. Calcd. forC₄₅H₄₆FN₇O₃: 751; found: 752 (M + H)⁺. 94-2(5R)-5-(((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- pyrrolidinone

LCMS: Anal. Calcd. for C₄₁H₄₄N₈O₃: 696; found: 697 (M + H)⁺. 94-31-((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1-phenylethyl)-4-methyl-4- piperidinol

LCMS: Anal. Calcd. for C₅₀H₅₆N₈O₃: 816; found: 817 (M + H)⁺. 94-4tert-butyl (4R)-4-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-1,3-thiazolidine-3-carboxylate

LCMS: Anal. Calcd. for C₄₅H₅₂N₈O₄S: 800; found: 801 (M + H)⁺. 94-5tert-butyl (1-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₅₆FN₈O₄: 796; found: 797 (M + H)⁺. 94-6N-(2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)benzamide

LCMS: Anal. Calcd. for C₄₅H₄₆FN₈O₃: 746; found: 747 (M + H)⁺. 94-7(1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(4-(4-methyl-1-piperazinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₄₈H₅₃N₉O₂: 787; found: 788 (M + H)⁺. 94-8(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((5-phenyl-2- thienyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₇H₄₅N₇O₂S: 771; found: 772 (M + H)⁺. 94-9(1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(4-(4-morpholinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₄₇H₅₀N₈O₃: 774; found: 775 (M + H)⁺. 94-10(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((4-phenyl-1,2,3-thiadiazol-5- yl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₅H₄₃N₉O₂S: 773; found: 774 (M + H)⁺. 94-11(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2-phenyl-1,3-thiazol-4- yl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₆H₄₄N₈O₂S: 772; found: 773 (M + H)⁺. 94-12tert-butyl 4-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-4-methyl-1-piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₈H₅₈N₈O₄: 810; found: 811 (M + H)⁺. 94-133-(2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)phenol

LCMS: Anal. Calcd. for C₄₄H₄₅N₇O₃: 719; found: 720 (M + H)⁺. 94-143-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-dimethyl-3-oxo-1-propanamine

LCMS: Anal. Calcd. for C₄₁H₄₈N₈O₂: 684; found: 685 (M + H)⁺. 94-15(4-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl) carbonyl)phenyl)methanol

LCMS: Anal. Calcd. for C₄₄H₄₅N₇O₃: 719; found: 720 (M + H)⁺. 94-16(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-indol-3-ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₅H₄₄N₈O₂: 728; found: 729 (M + H)⁺. 94-17(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3R)-1-benzyl-3-pyrrolidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₄₈H₅₂N₈O₂: 772; found: 773 (M + H)⁺. 94-18tert-butyl (2S)-2-(2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxoethyl)-1-pyrrolidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₄: 796; found: 797 (M + H)⁺. 94-19(1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((5-methyl-1H-pyrazol-3-yl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₄₂H₄₅N₉O₂: 707; found: 708 (M + H)⁺. 94-20tert-butyl (2R)-2-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-1-piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₄: 796; found: 797 (M + H)⁺. 94-21tert-butyl ((1S,3R)-3-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₄: 796; found: 797 (M + H)⁺. 94-22(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3-(1-piperidinyl)propanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₄H₅₂N₈O₂: 724; found: 725 (M + H)⁺. 94-23(2-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-1-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl) carbonyl)phenyl)phenyl)methanone

LCMS: Anal. Calcd. for C₅₀H₄₇N₇O₃: 793; found: 794 (M + H)⁺. 94-24(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-methoxyphenoxy)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₅H₄₇N₇O₄: 749; found: 750 (M + H)⁺. 94-25tert-butyl 3-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-1-azetidinecarboxylate

LCMS: Anal. Calcd. for C₄₅H₅₂N₈O₄: 768; found: 769 (M + H)⁺. 94-26(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3S)-1-benzyl-3-pyrrolidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₄₈H₅₂N₈O₂: 772; found: 773 (M + H)⁺. 94-27(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3-(1-pyrrolidinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₇H₅₀N₈O₂: 758; found: 759 (M + H)⁺. 94-28tert-butyl (2-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl) phenyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₂N₈O₄: 804; found: 805 (M + H)⁺. 94-29tert-butyl (3R)-3-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-1-piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₄: 796; found: 797 (M + H)⁺. 94-30(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-(1-((1-(trifluoromethyl) cyclopropyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₁H₄₂F₃N₇O₂: 721; found: 722 (M + H)⁺. 94-314-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-N,N-dimethylaniline

LCMS: Anal. Calcd. for C₄₅H₄₈N₈O₂: 732; found: 733 (M + H)⁺. 94-32(3-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)phenyl)phenyl)methanone

LCMS: Anal. Calcd. for C₅₀H₄₇N₇O₃: 793; found: 794 (M + H)⁺. 94-33tert-butyl (cis-4-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)cyclohexyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₈N₈O₄: 810; found: 811 (M + H)⁺. 94-34′tert-butyl 4-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-1-piperidinecarboxylate

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₄: 796; found: 797 (M + H)⁺. 94-35tert-butyl (cis-4-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-1-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)cyclohexyl)carbamate

LCMS: Anal. Calcd. for C₄₈H₅₈N₈O₄: 810; found: 811 (M + H)⁺. 94-36(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (diphenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2- oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₅₀H₄₉N₇O₂: 779; found: 780 (M + H)⁺. 94-375-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-5-oxo-2- pentanone

LCMS: Anal. Calcd. for C₄₁H₄₅N₇O₃: 683; found: 684 (M + H)⁺. 94-38(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (2-fluorobenzoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₃H₄₂FN₇O₂: 707; found: 708 (M + H)⁺. 94-39(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (2-biphenylylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₉H₄₇N₇O₂: 765; found: 766 (M + H)⁺. 94-40(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (2-benzylbenzoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₅₀H₄₉N₇O₂: 779; found: 780 (M + H)⁺. 94-414-((1E)-3-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-3-oxo-1-propen-1-yl)-N,N-dimethylaniline

LCMS: Anal. Calcd. for C₄₇H₅₀N₈O₂: 758; found: 759 (M + H)⁺. 94-42(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-thiazol-4-ylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₀H₄₀N₈O₂S: 696; found: 697 (M + H)⁺. 94-43(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((((1R,2S,5R)-2-isopropyl-5-methylcylcohexyl)oxy)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1-phenylethanamine

LCMS: Anal. Calcd. for C₄₈H₅₉N₇O₃: 781; found: 782 (M + H)⁺. 94-441-(6-chloro-3-pyridinyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-dimethyl-2-oxoethanamine

LCMS: Anal. Calcd. for C₄₅H₄₈ClN₉O₂: 781; found: 782 (M + H)⁺. 94-452-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-1-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-(3-pyridinyl)ethanamine

LCMS: Anal. Calcd. for C₄₅H₄₉N₉O₂: 747; found: 748 (M + H)⁺. 94-462-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-1-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-(2-pyridinyl)ethanamine

LCMS: Anal. Calcd. for C₄₅H₄₉N₉O₂: 747; found: 748 (M + H)⁺. 94-47(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(2-thienylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₂H₄₃N₇O₂S: 709; found: 710 (M + H)⁺. 94-48(1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3-thienylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₂H₄₃N₇O₂S: 709; found: 710 (M + H)⁺. 94-49(1R)-N,N-dimethyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(1-naphthylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₈H₄₇N₇O₂: 753; found: 754 (M + H)⁺. 94-50(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-imidazol-5-ylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₁H₄₃N₉O₂: 693; found: 694 (M + H)⁺. 94-51(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-fluorophenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₄H₄₄FN₇O₂: 721; found: 722 (M + H)⁺. 94-52(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-fluorophenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₄H₄₄FN₇O₂: 721; found: 722 (M + H)⁺. 94-53(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4-fluorophenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₄H₄₄FN₇O₂: 721; found: 722 (M + H)⁺. 94-54(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1-benzothiophen-3-ylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₆H₄₅N₇O₂S: 759; found: 760 (M + H)⁺. 94-55(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1,2-benzisoxazol-3-ylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₅H₄₄N₈O₃: 744; found: 745 (M + H)⁺. 94-56(1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-indol-3-ylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₆H₄₆N₈O₂: 742; found: 743 (M + H)⁺.

Examples 95-103

      Example       Compound Name

Retention time (LC- Condition); homogeneity index MS data 952-((2S)-1-((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1- ((2S)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol

1.16 minutes (Cond. 1); >98%; LC/MS Anal. Calcd. for [M + H]⁺C₄₃H₄₈N₇O₃: 710.38; found 710.60 96 4-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- phenyl-2-(1-pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl) morpholine

1.82 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₅N₈O₃: 815.44; found 815.45; HRMS: Anal. Calcd. for [M + H]⁺C₅₀H₅₅N₈O₃: 815.4397; found 815.4395 97 1-(2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2- (1-pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)-4- piperidinol

1.79 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₁H₅₇N₈O₃: 829.46; found 829.43; HRMS: Anal. Calcd. for [M + H]⁺C₅₁H₅₇N₈O₃: 829.4554; found 829.4585 98 1-methyl-4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl) piperazine

1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₁H₅₈N₉O₂: 828.47; found 828.45; HRMS: Anal. Calcd. for [M + H]⁺C₅₁H₅₈N₉O₂: 828.4713; found 828.4722 99 (1R)-N,N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-phenyl-2-(1-pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine

1.86 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₇N₈O₂: 801.46; found 801.44; HRMS: Anal. Calcd. for [M + H]⁺C₅₀H₅₇N₈O₂: 801.4604; found 801.4595 100 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl) carbamate

1.93 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₁N₈O₄:803.40; found 803.47; HRMS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₁N₈O₄:803.4033; found 803.4058 101 methyl ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl) carbamate

1.80 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₉N₈O₄:741.39; found 741.33; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₉N₈O₄:741.3877; found 741.3900 102 methyl (2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl) carbamate

1.80 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₇N₈O₄:727.37; found 727.24; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₇N₈O₄:727.3720; found 727.3743 103 (2S)-N,N-dimethyl-1-oxo-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2- propanamine

1.69 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₂:711.41; found 711.37; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₂:711.4135; found 711.4154

Examples 103-1 to 103-12

103-1 1-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-4-phenylpiperidine

RT = 4.80 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₀H₅₃N₇O₃ 800.03 Found: 800.49 (M + H)⁺ 103-21-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-4-phenylpiperidine

RT = 4.59 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₀H₅₃N₇O₃ 800.03 Found: 800.48 (M + H)⁺ 103-31-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl) piperazine

RT = 3.36; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, oneminute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B =10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for:C₄₄H₅₀N₈O₃ 738.94 Found: 739.49 (M + H)⁺ 103-41-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)piperazine

RT = 3.47 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₄₄H₅₀N₈O₃ 738.94 Found: 739.51 (M + H)⁺ 103-5 benzyl4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-1-piperazinecarboxylate

RT = 5.00 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₁H₅₄N₈O₅ 859.05 Found: 859.51 (M + H)⁺ 103-6 benzyl4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-1-piperazinecarboxylate

RT = 5.10 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₅₁H₅₄N₈O₅ 859.05 Found: 859.49 (M + H)⁺ 103-71-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl) piperazine

RT = 3.61 minutes; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes,one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid,B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd.for: C₄₃H₄₈N₈O₃ 724.91 Found: 725.47 (M + H)⁺ 103-8 4-(2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)- 2-piperazinone

RT = 3.97; HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, oneminute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B =10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for:C₄₃H₄₆N₈O₄ 738.90 Found: 739.56 (M + H)⁺ 103-9 1-methyl-3-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4′-(2- ((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)urea

HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 4 minutes, 1 minute holdtime, A = 90% water, 10% methanol, 0.2% H₃PO₄, B = 10% water, 90%methanol, 0.2% H₃PO₄, RT = 1.81 minutes, 96% homogeneity index.; LCMS:Anal. Calcd. for C₄₁H₄₄N₈O₄: 712.84; found: 713.37 (M + H)⁺; HRMS: Anal.Calcd. for C₄₁H₄₅N₈O₄ 713.3564; found: 713.3564 (M + H)⁺. 103-101-ethyl-3-((1R)-2-oxo-1- phenyl-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)urea

HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute holdtime, A = 90% water, 10% methanol, 0.2% H₃PO₄, B = 10% water, 90%methanol, 0.2% H₃PO₄, RT = 1.88 minutes, 95% homogeneity index; LCMS:Anal. Calcd. for C₄₂H₄₆N₈O₄: 726.87; found: 727.71 (M + H)⁺; HRMS: Anal.Calcd. for C₄₂H₄₇N₈O₄ 727.3720; found: 727.3695 (M + H)⁺. 103-111-cyclopentyl-3-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)urea

HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute holdtime, A = 90% water, 10% methanol,0.2% H₃PO₄, B = 10% water, 90%methanol, 0.2% H₃PO₄, RT = 2.11 minutes, 96% homogeneity index; LCMS:Anal. Calcd. for C₄₅H₅₀N₈O₄: 766.93; found: 767.45 (M + H)⁺; HRMS: Anal.Calcd. for C₄₅H₅₁N₈O₄ 767.4033; found: 767.4032 (M + H)⁺. 103-121,1-dimethyl-3-((1R)-2-oxo-1- phenyl-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)urea

HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute holdtime, A = 90% water, 10% methanol, 0.2% H₃PO₄, B = 10% water, 90%methanol, 0.2% H₃PO₄, RT = 1.87 minutes, 97% homogeneity index; LCMS:Anal. Calcd. for C₄₂H₄₆N₈O₄: 726.87; found: 727.38 (M + H)⁺; HRMS: Anal.Calcd. for C₄₂H₄₇N₈O₄ 727.3720; found: 727.3723 (M + H)⁺.

Examples 104-107

      Example       Compound Name

Retention time (LC- Condition); homogeneity index MS data 1041-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)piperazine

1.12 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₅₁N₈O₃: 739.41; found 739.63; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₅₁N₈O₃: 739.4084; found 739.4054 105 4-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)- tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)morpholine

1.13 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₈N₇O₄: 726.38; found 726.63; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₄₈N₇O₄: 726.3768; found 726.3803 106 (1R)-N,N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethanamine

1.12 minutes (Cond. 1); >97%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₅₀N₇O₃: 712.40; found 712.45; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₅₀N₇O₃: 712.3975; found 712.3998 107 (1R)-N-ethyl-N-methyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethanamine

1.10 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₈N₇O₃: 698.38; found 698.45; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₈N₇O₃: 698.3819; 698.3823

Examples 107-1 to 107-30

Example Number Compound Name Structure Data Example 107-1 (1S)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2-phenyl- 2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl acetate

¹HNMR (400 MHz, CDCl₃) δ 7.63-7.85 (m, 8H), 7.48-7.54 (m, 2H), 7.26-7.46(m, 7H), 6.94-7.17 (m, 3H), 6.22 and 6.18 (s, 1H, rotamers, 1:1), 5.99and 5.68 (s, 1H, rotamers, 1:1), 5.61 and 5.54 (d, J = 7.8 Hz, 1H,rotamers, 1:1), 5.20-5.23 and 5.10-5.13 (m, 1H, rotamers, 1:1), 4.46 and4.43 (s, 1H, rotamers, 1:1), 3.97-4.06 (m, 1H), 3.89-3.93 and 3.78-3.84(m, 1H, rotamers, 1:1), 3.63-3.72 and 3.46-3.60 (m, 1H, rotamers, 1:1),3.23-3.32 (m, 2H), 2.41-2.59 (m, 4H), 2.13-2.26 (m, 2H), 2.11 and 2.10(s, 3H, rotamers, 1:1), 2.05-2.09 (m, 2H), 1.97-1.98 (m, 1H), 1.82-1.90(m, 1H), 1.58 (br s, 4H), 1.45 (br s, 2H); LCMS: Anal. Calcd. forC₄₉H₅₁N₇O₄: 801; found: 802 (M + H)⁺. Example 107-2 4-methyl-1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)- 4-piperidinol

LCMS: Anal. Calcd. for C₅₃H₆₀N₈O₃: 856; found: 857 (M + H)⁺. Example107-3 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-(2- fluorobenzoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₆H₅₆FN₇O₂: 747; found: 748 (M + H)⁺. Example107-4 N,N-dimethyl-4- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)aniline

LCMS: Anal. Calcd. for C₄₈H₅₂N₈O₂: 772; found: 773 (M + H)⁺. Example107-5 5-oxo-5-((2S)-2- (5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- pentanone

LCMS: Anal. Calcd. for C₄₄H₄₉N₇O₃: 723; found: 724 (M + H)⁺. Example107-6 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1- (diphenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₅₃H₅₃N₇O₂: 819; found: 820 (M + H)⁺. Example107-7 1-(3-oxo-3-((2S)- 2-(5-(4′-(2-((2S)- 1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) propyl)piperidine

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₂: 764; found: 765 (M + H)⁺. Example107-8 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2- methoxyphenoxy)acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₈H₅₁N₇O₂:789; found: 790 (M + H)⁺. Example107-9 tert-butyl 4- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-1- piperidine-carboxylate

LCMS: Anal. Calcd. for C₅₀H₆₀N₈O₄: 836; found: 837 (M + H)⁺. Example107-10 4-(4-(((2S)-2-(5- (4′-(2-((2S)-1- ((2R)-2-phenyl- 2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)phenyl)morpholine

LCMS: Anal. Calcd. for C₅₀H₅₄N₈O₃: 814; found: 815 (M + H)⁺. Example107-11 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(1,3-triazol-4- ylcarbonyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine

LCMS: Anal. Calcd. for C₄₃H₄₄N₈O₂S: 736; found: 737 (M + H)⁺. Example107-12 tert-butyl 3- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-1-azetidinecarboxylate

LCMS: Anal. Calcd. for C₄₈H₅₆N₈O₄: 808; found: 809 (M + H)⁺. Example107-13 tert-butyl (cis-4- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclohexyl) carbamate

LCMS: Anal. Calcd. for C₅₁H₆₂N₈O₄: 850; found: 851 (M + H)⁺. Example107-14 tert-butyl 4- methyl-4-(((2S)- 2-(5-(4′-(2-((2S)- 1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-1-piperidinecarboxylate

LCMS: Anal. Calcd. for C₅₁H₆₂N₈O₄: 850; found: 851 (M + H)⁺. Example107-15 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((1-(trifluoromethyl) cyclopropyl) carbonyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl) piperidine

LCMS: Anal. Calcd. for C₄₄H₄₆F₃N₇O₂: 761; found: 762 (M + H)⁺. Example107-16 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((5-methyl-1H- pyrazol-3-yl)acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₅H₄₉N₉O₂: 747; found: 748 (M + H)⁺. Example107-17 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-(((3R)-1- benzyl-3-pyrrolidinyl)- carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)piperidine

LCMS: Anal. Calcd. for C₅₁H₅₆N₈O₂: 812; found: 813 (M + H)⁺. Example107-18 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-(((3S)-1- benzyl-3-pyrrolidinyl)- carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)piperidine

LCMS: Anal. Calcd. for C₅₁H₅₆N₈O₂: 812; found: 813 (M + H)⁺. Example107-19 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2R)-2- methoxy-2-phenylacetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₈H₅₁N₇O₃: 773; found: 774 (M + H)⁺. Example107-20 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2S)-2- methoxy-2-phenylacetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₈H₅₁N₇O₃: 773; found: 774 (M + H)⁺. Example107-21 (1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-2-phenyl- 2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl acetate

LCMS: Anal. Calcd. for C₄₉H₅₁N₇O₄: 801; found: 802 (M + H)⁺. Example107-22 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((1-phenylcyclopropyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine

LCMS: Anal. Calcd. for C₄₉H₅₁N₇O₂: 769; found: 770 (M + H)⁺. Example107-23 N,N-dimethyl-1- (2-(2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) ethyl)phenyl methanamine

LCMS: Anal. Calcd. for C₅₀H₅₆N₈O₂: 800; found: 801 (M + H)⁺. Example107-24 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((3-methyl-5-isoxazolyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)piperidine

LCMS: Anal. Calcd. for C₄₅H₄₈N₈O₃: 748; found: 749 (M + H)⁺. Example107-25 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2-methyl-1,3-thiazol-4-yl) acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)piperidine

LCMS: Anal. Calcd. for C₄₅H₄₈N₈O₂S: 764; found: 765 (M + H)⁺. Example107-26 4-(2-(2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) benzyl)morpholine

LCMS: Anal. Calcd. for C₅₂H₅₈N₈O₃: 842; found: 843 (M + H)⁺. Example107-27 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2-(1-pyrrolidinylmethyl) phenyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) ethyl)piperidine

LCMS: Anal. Calcd. for C₅₂H₅₈N₈O₂:826; found: 827 (M + H)⁺. Example107-28 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2- fluorophenyl)acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₇H₄₈FN₇O₂: 800; found: 801 (M + H)⁺. Example107-29 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-acetyl-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl) piperidine

LCMS: Anal. Calcd. for C₄₁H₄₅FN₇O₂: 667; found: 668 (M + H)⁺. Example107-30 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(2-thienylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine

LCMS: Anal. Calcd. for C₄₅H₄₇N₇O₂: 749; found: 750 (M + H)⁺.

Example 107-31 to 107-34

Examples 107-31 through 107-34 were prepared in similar fashion toexample 28. Cap-38 was appended to intermediate 28d, the Boc carbamatewas removed with TFA or HCl and the appropriate carboxylic acid wascoupled.

Example Compound Name Structure Data Example 107-31(1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-(2-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₄₆H₄₉FN₈O₂: 764; found: 765 (M + H)⁺. Example107-32 (1R)-1-(2-fluorophenyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-methoxy-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxoethanamine

LCMS: Anal. Calcd. for C₄₅H₄₆FN₇O₃: 751; found: 752 (M + H)⁺. Example107-33 (1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-(2-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl acetate

LCMS: Anal. Calcd. for C₄₆H₄₆FN₇O₄: 779; found: 780 (M + H)⁺. Example107-34 (1R)-1-(2-fluorophenyl)- N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1- ((1-phenyl- cyclopropyl) carbonyl)-2-pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethanamine

LCMS: Anal. Calcd. for C₄₆H₄₆FN₇O₂: 747; found: 748 (M + H)⁺.

Example 107-35 to 107-38

Examples 107-35 through 107-38 were prepared in similar fashion toexample 28. Cap-39 was appended to intermediate 28d, the Boc carbamatewas removed with TFA or HCl and the appropriate carboxylic acid wascoupled.

Example Compound Name Structure Data Example 107-35(1R)-1-(2-chlorophenyl)- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)- N,N-dimethyl-2-oxoethanamine

LCMS: Anal. Calcd. for C₄₆H₄₉ClN₈O₂: 780; found: 781 (M + H)⁺. Example107-36 methyl ((1R)-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-2-(2-chlorophenyl)-2- (dimethylamino)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇ClN₈O₄: 810; found: 811 (M + H)⁺. Example107-37 (1R)-1-(2-chlorophenyl)- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-methoxy-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2- oxoethanamine

LCMS: Anal. Calcd. for C₄₄H₄₆ClN₇O₃: 767; found: 768 (M + H)⁺. Example107-38 (1R)-1-(2-chlorophenyl)- N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethanamine

LCMS: Anal. Calcd. for C₄₁H₄₄ClN₇O₃: 717; found: 718 (M + H)⁺.

Example 107-39 to 107-43

Examples 107-39 through 107-44 were prepared in similar fashion toexample 28. Cap-40 was appended to intermediate 28d, the Boc carbamatewas removed with TFA or HCl and the appropriate carboxylic acid wascoupled.

Example Compound Name Structure Data Example 107-39 methyl ((1R)-1-(2-chlorophenyl)-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl) carbamate

¹H NMR (400 MHz, CD₃OD) δ 7.58-7.77 (m, 8 H), 7.42-7.55 (m, 2 H), 7.19-7.39 (m, 4 H), 5.94 and 5.89 (s, 1 H, rotamers, 1:1), 5.80 and 5.61 (s,1 H, rotamers, 1:1), 5.43-5.47 and 5.35-5.38 (m, 1 H, rotamers, 1:1),5.20-5.24 (m, 1 H), 5.15-5.18 (m, 1 H), 4.67- 4.70 and 4.39- 4.42 (m, 1H, rotamers, 1:1), 3.92-3.98 (m, 1 H), 3.85-3.90 (m, 1 H), 3.69- 3.84(m, 2 H), 3.64 and 3.63 (s, 3 H, rotamers, 1:1), 3.53-3.59 (m, 1 H),2.35- 2.46 (m, 1 H), 2.21-2.29 (m, 2 H), 2.06-2.17 (m, 3 H), 1.84- 2.01(m, 4 H), 1.66-1.76 and 1.41-1.47 (m, 1 H, rotamers, 1:1); LCMS: Anal.Calcd. for C₄₁H₄₂ClN₇O₅: 747; found 748 (M + H)⁺. Example 107-40 methyl((1R)-1-(2- chlorophenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxoethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₇ClN₈O₄: 810; found: 811 (M + H)⁺. Example107-41 methyl ((1R)-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(2-chlorophenyl)-2- ((methoxycarbonyl)amino) acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenyl)ethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₅ClN₈O₆: 840; found: 841 (M + H)⁺. Example107-42 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(4- hydroxy-4-methyl-1- piperidinyl)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₅₃ClN₈O₅: 880; found: 881 (M + H)⁺. Example107-43 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- methoxy-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₄ClN₇O₅: 797; found: 798 (M + H)⁺. Example107-44 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(2- chlorophenyl)-2- (dimethylamino)acetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₄₆Cl₂N₈O₄: 844; found: 845 (M + H)⁺.

Example 108 methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(ethylcarbamoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Ethyl isocyanate (5 μL, 0.063 mmol) was added to a methanol (1.0 mL)solution of 28f (30 mg, 0.049 mmol) and stirred at ambient condition for1.8 hours. The residue was treated with 2.0 M NH₃/methanol (2 mL) andstirred for an additional 30 minutes, and all the volatile componentswere removed in vacuo. The resulting material was purified by a reversephase HPLC (H₂O/methanol/TFA) to provide the TFA salt of Example 108 asa light yellow foam (16.7 mg) LC: 1.95 minutes (Cond. 2); >98%homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C₃₉H₄₃N₈O₄: 687.34.found 687.53; HRMS: Anal. Calcd. for [M+H]⁺ C₃₉H₄₃N₈O₄: 687.3407. found687.3417.

Example 109 dibenzyl(2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

Example 109 Step a benzyl(2S)-2-(5-(4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

The Boc-deprotection of 28c using the procedure described for thesynthesis of pyrrolidine 1e from carbamate 1d provided 109a. RT=1.92minutes (Cond 2); >98% homogeneity index; LC/MS: Anal. Calcd.C₃₄H₃₅N₆O₂: 559.28. found 559.44

Example 109 dibenzyl(2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

Benzyl chloroformate (10.5 μL, 0.0736 mmol) was added to a THF (2.0 mL)solution of 109a (37.1 mg, 0.664 mmol) and triethylamine (15 μl, 0.107mmol), and stirred under ambient conditions for 6 hours. The volatilecomponent was removed in vacuo, and the residue was treated with 2NNH₃/methanol (2 mL) and stirred for 15 minutes. The volatile componentwas removed in vacuo, and the residue purified by a reverse phase HPLC(H₂O/methanol/TFA) to provide the TFA salt of Example 109 as anoff-white foam (37.9 mg). LC (Cond. 2): RT=2.25 min; >98% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₄₁N₆O₄: 693.32. found 693.59;HRMS: Anal. Calcd. for [M+H]⁺ C₄₂H₄₁N₆O₄: 693.3189. found 693.3220.

Example 110(2R)—N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)tetrahydro-2-furancarboxamide

Example 110 Step a(1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

Amine 110a was synthesized starting from 28d and(S)-tetrahydrofuran-2-carboxylic by sequentially employing proceduresdescribed in the preparation of 28f (from 28d) and 25b (from 1e). LC(Cond. 1): RT=1.13 min; >98% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺ C₃₉H₄₂N₇O₃: 656.34. found 656.49; HRMS: Anal. Calcd. for [M+H]⁺C₃₉H₄₂N₇O₃: 656.3349. found 656.3377.

Example 110(2R)—N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)tetrahydro-2-furancarboxamide

Example 110 (TFA salt) was prepared from Example 110a and(S)-tetrahydrofuran-2-carboxylic acid using the conditions described forthe synthesis Example 1 from amine 1e. LC (Cond. 1): RT=1.28 min; >98%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₄H₄₈N₇O₅: 754.37.found 754.60; HRMS: Anal. Calcd. for [M+H]⁺ C₄₄H₄₈N₇O₅: 754.3717. found754.3690.

Example 111N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)-4-morpholinecarboxamide

Example 111 (TFA salt) was prepared from amine 110a and morpholine4-carbonyl chloride using the procedure described for the synthesis ofExample 29 from amine 28f. LC (Cond. 1): RT=1.28 min; >98% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₄H₄₉N₈O₅: 769.38. found 769.60.

Using similar methods described for the preparation of Example 111, thefollowing compounds (Example 112-120) were synthesized as TFA salts.

Example 112-117

    Example     Compound Name

Retention time (LC-Condition); homogeneity index MS data 112(2S)-N-((1R)-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro- 2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl) tetrahydro-2- furancarboxamide

1.28 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₈N₇O₅: 754.37; found 754.59; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₄₈N₇O₅: 754.3717; found 754.3731 113 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)- tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)- L-prolinamide

1.14 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₅₁N₈O₄: 767.40; found 767.68; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₅₁N₈O₄: 767.4033; found 767.4035 114 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)- tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)- 4-piperidinecarboxamide

1.12 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₆H₅₃N₈O₄: 781.42; found 781.67; HRMS: Anal. Calcd. for [M + H]⁺C₄₆H₅₃N₈O₄: 781.4190; found 781.4195 115 N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2S)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl) tetrahydro-2H- pyran-4- carboxamide

1.24 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₅H₅₀N₇O₅: 768.39; found 768.66; HRMS: Anal. Calcd. for [M + H]⁺C₄₅H₅₀N₇O₅: 768.3873; found 768.3897 116 (4R)-4-fluoro-1-methyl-N-((1R)-2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)- L-prolinamide

1.16 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₅H₅₀FN₈O₄: 785.39; found 785.63; HRMS: Anal. Calcd. for [M + H]⁺C₄₅H₅₀FN₈O₄: 785.3939; found 785.3940 117 4-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)- tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)-1- piperazinecarboxamide

1.15 minutes (Cond. 1); 97.6%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₅H₅₂N₉O₄: 782.41; found 782.64; HRMS: Anal. Calcd. for [M + H]⁺C₄₅H₅₂N₉O₄: 782.4142; found 782.4161

Examples 118 to 120-9

Examples 118 to 120-9 were prepared as described in the preparation ofExample 110a substituting (R)-tetrahydrofuryl carboxylic acid and theappropriate carboxylic acid, carboxylic acid chloride, carbamoylchloride, or isocyanate.

    Example     Compound Name

Retention time (LC- Condition); homogeneity index; MS data 118N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)acetamide

1.89 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄N₇O₄: 698.35; found 698.25; HRMS: Anal. Calcd. for [M + H]⁺C₄₁H₄₄N₇O₄: 698.3455; found 698.3474 119 (2R)-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)tetrahydro- 2-furancarboxamide

1.99 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₈N₇O₅: 754.37; found 754.28; [M + H]⁺ C₄₄H₄₈N₇O₅: 754.3717; found754.3705 120 N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-4-morpholinecarboxamide

2.00 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₉N₈O₅: 769.38; found 769.32 120-5 1-methyl-N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)-1H- imidazole-5-carboxamide

RT = 4.02 (97%); HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H₃PO₄, B= 10% water, 90% methanol, 0.2% H₃PO₄, RT = 1.87 minutes, 97%homogeneity index; LCMS: Anal. Calcd. for: C₄₄H₄₅N₉O₄ 763.91; Found:764.52 (M + H)⁻ 120-6 1-methyl-N-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol- 4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) ethyl)-L- prolinamide

RT = 3.68 (99%); HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H₃PO₄, B= 10% water, 90% methanol, 0.2% H₃PO₄, RT = 1.87 minutes, 97%homogeneity index; LCMS: Anal. Calcd. for: C₄₅H₅₀N₈O₄ 766.95; Found:767.47 (M + H)⁻ 120-7 N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-2-(3-pyridinyl)acetamide

RT = 3.81 (99%); HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H₃PO₄, B= 10% water, 90% methanol, 0.2% H₃PO₄, RT = 1.87 minutes, 97%homogeneity index; LCMS: Anal. Calcd. for: C₄₆H₄₆N₈O₄ 774.93; Found:775.47 (M + H)⁻ 120-8 N²,N²-dimethyl-N-((1R)- 2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol- 4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl)glycinamide

¹H NMR (500 MHz, DMSO- d₆) δ ppm 1.71-2.44 (m, 12 H), 2.65-2.89 (m, 6H), 3.04-3.21 (m, J = 8.55 Hz, 1 H), 3.46-3.68 (m, 1 H), 3.64- 4.07 (m,6 H), 4.64 (dd, J = 8.09, 5.34 Hz, 1 H), 5.09- 5.30 (m, 2 H), 5.66-5.86(m, 1 H), 7.32-7.49 (m, 4 H), 7.82- 8.22 (m, 10 H), 9.15-9.38 (m, 1 H),9.68 (s, 1 H), 14.60 (s, 2 H); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over10 minutes, one minute hold time A = 90% water, 10% methanol, 0.2%phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT =3.61 min; LCMS: Anal. Calcd. for: C₅₂H₅₆N₁₀O₆ 740.91; Found: 741.48 (M +H)⁻. 120-9 1-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-3-(3-pyridinyl)urea

¹H NMR (500 MHz, DMSO- d₆) δ ppm 1.64-2.40 (m, 12 H), 3.11-3.27 (m, 1H), 3.51-3.65 (m, 1 H), 3.80 (dd, J = 18.46, 6.87 Hz, 3 H), 3.96- 4.11(m, 1 H), 4.64 (dd, J = 7.78, 5.34 Hz, 1 H), 5.13- 5.23 (m, 1 H),5.21-5.35 (m, 1 H), 5.66 (d, J = 7.02 Hz, 1 H), 7.29-7.57 (m, 7 H),7.82-8.07 (m, 10 H), 8.14 (s, 1 H), 8.22 (d, J = 4.58 Hz, 1 H), 8.68 (s,1 H), 9.32 (s, 1 H), 14.46 (s, 2 H); HPLC Xterra 4.6 × 50 mm,0 to 100% Bover 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2%phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT =3.83 min; LCMS: Anal. Calcd. for: C₄₅H₄₅N₉O₄ 775.92; Found: 776.53 (M +H)⁻.

Example 121(1R,1′R)-2,2′-((2,2′-dimethyl-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 121 Step a-b

PdCl₂(Ph₃P)₂ (257 mg, 0.367 mmol) was added to a dioxane (45 mL)solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) andtri-n-butyl(1-ethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at80° C. for 17 hours. The reaction mixture was treated with water (15mL), cooled to ˜0° C. (ice/water), and then NBS (1.839 g, 10.3 mmol) wasadded in batches over 7 minutes. After about 25 minutes of stirring, thevolatile component was removed in vacuo, and the residue was partitionedbetween CH₂Cl₂ and water. The aqueous layer was extracted with CH₂Cl₂,and the combined organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting crude material was purified by agravity chromatography (silica gel; 4% ethyl acetate/hexanes) to providebromide 121a as a brownish-yellow solid (2.699 g); the sample is impureand contains stannane-derived impurities, among others. ¹H NMR (CDCl₃,δ=7.24, 400 MHz): 7.83 (s, 1H), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s,3H).

A CH₃CN (15 mL) solution of 121a (2.69 g, <9.21 mmol) was added dropwiseover 3 minutes to a CH₃CN (30 mL) solution of (S)-Boc-proline (2.215 g,10.3 mmol) and triethylamine (1.40 mL, 10.04 mmol), and stirred for 90minutes. The volatile component was removed in vacuo, and the residuewas partitioned between water and CH₂Cl₂, and the organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo. The resulting crudematerial was purified by a flash chromatography (silica gel; 15-20%ethyl acetate/hexanes) to provide 121b as a colorless viscous oil (2.74g). ¹H NMR (DMSO-d₆, δ=2.50, 400 MHz): δ 7.98 (m, 1H), 7.78 (d, J=8.3,1H), 7.72-7.69 (m, 1H), 5.61-5.41 (m, 2H), 4.35-4.30 (m, 1H), 3.41-3.30(m, 2H), 2.43 (s, 3H), 2.33-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36(s, 9H); LC (Cond. 1): RT=1.91 min; >95% homogeneity index; LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₉H₂₄BrNNaO₅ 448.07. found 448.10.

Additional keto-esters can be prepared in analogous fashion.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Structure Data 121b-1

RT = 2.15 minutes (condition 2, 98%); LRMS: Anal. Calcd. for C₁₇H₂₂NO₅399.07; found: 400.10 (M + H)⁺. 121b-2

RT = 2.78 minutes (condition 1, 90%); LRMS: Anal. Calcd. for C₂₀H₂₀³⁷BrNO₅ 435.05 found: 458.02 (M + Na)⁺.

Example 121 Step c

A mixture of ketoester 121b (1.445 g, 3.39 mmol) and NH₄OAc (2.93 g,38.0 mmol) in xylenes (18 mL) was heated with a microwave at 140° C. for80 minutes. The volatile component was removed in vacuo, and the residuewas carefully partitioned between CH₂Cl₂ and water, where enoughsaturated NaHCO₃ solution was added to neutralize the aqueous medium.The aqueous phase was extracted with CH₂Cl₂, and the combined organicphase was dried (MgSO₄), filtered, and concentrated in vacuo. The crudeproduct was purified by a flash chromatography (silica gel, 40% ethylacetate/hexanes) to provide imidazole 121c as an off-white solid (1.087g). ¹H NMR (DMSO-d₆, δ=2.50, 400 MHz): 12.15/11.91/11.84 (br s, 1H),7.72-7.24 (m, 4H), 4.78 (m, 1H), 3.52 (m, 1H), 3.38-3.32 (m, 1H), 2.35(s, 3H), 2.28-1.77 (m, 4H), 1.40/1.14 (s, 9H); LC (Cond. 1): RT=1.91min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₉H₂₅BrN₃O₂405.96. found 406.11.

Example 121 Step d

PdCl₂dppf.CH₂Cl₂ (50.1 mg, 0.061 mmol) was added to a pressure tubecontaining a mixture of bromide 121c (538.3 mg, 1.325 mmol),bis(pinacolato)diboron (666.6 mg, 2.625 mmol), potassium acetate (365.8mg, 3.727 mmol) and DMF (10 mL). The reaction mixture was flushed withN₂ and heated at 80° C. for 24.5 hours. The volatile component wasremoved in vacuo and the residue was partitioned between CH₂Cl₂ andwater, where enough saturated NaHCO₃ solution was added to make the pHof the aqueous medium neutral. The aqueous phase was extracted withCH₂Cl₂, and the combined organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting material was purified by a Biotagesystem (silica gel, 40-50% ethyl acetate/hexanes) to provide boronate121d as a white foam (580 mg). According to ¹H NMR the sample containsresidual pinacol in a product/pinacol ratio of ˜3. ¹H NMR (DMSO-d₆,δ=2.50, 400 MHz): δ 12.16/11.91/11.83 (br s, 1H), 7.63-7.25 (m, 4H),4.78 (m, 1H), 3.53 (m, 1H), 3.39-3.32 (m, 1H), 2.48/2.47 (s, 3H),2.28-1.78 (m, 4H), 1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H); LC (Cond.1): RT=1.62 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₅H₃₇BN₃O₄ 454.29.found 454.15

Example 121 Step e and Example 121 Step f

Carbamate 121e was prepared from bromide 121c and boronate 121daccording to the preparation of dimer 1d; LC (Cond. 1): RT=1.43 min;LC/MS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₉N₆O₄ 653.38. found 653.65.

The deprotection of carbamate 121e, according to the preparation ofpyrrolidine 1e, provided 121f as an off-white foam. ¹H NMR (DMSO-d₆,s=2.50, 400 MHz): 11.79 (br s, 2H), 7.66 (s, 2H), 7.57 (d, J=7.8, 2H),7.41 (br s, 2H), 7.02 (d, J=7.8, 2H), 4.15 (app t, J=7.2, 2H), 3.00-2.94(m, 2H), 2.88-2.82 (m, 2H), 2.09-2.01 (m, 2H), 2.04 (s, 6H), 1.93-1.85(m, 2H), 1.82-1.66 (m, 4H). Note: although broad signals correspondingto the pyrrolidine NH appear in the 2.8-3.2 ppm region, the actual rangefor their chemical shift could not be determined. LC (Cond. 1): RT=1.03min; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₈H₃₃N₆ 453.28. found 453.53

Example 121(1R,1′R)-2,2′-((2,2′-dimethyl-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 121 (TFA salt) was synthesized from 121f according to thepreparation of Example 1 from 1e; LC (Cond. 1): RT=1.14 min; >98%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₈H₅₅N₈O₂ 775.45;775.75; HRMS: Anal. Calcd. for [M+H]⁺ C₄₈H₅₅N₈O₂ 775.4448. found775.4473

Example 122 dimethyl((2,2′-dimethyl-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

Example 122 (TFA salt) was prepared from pyrrolidine 121f and Cap-4 byusing the procedure described for the preparation of Example 1 frompyrrolidine 1e. LC (Cond. 1): RT=1.35 min; >98% homogeneity index; HRMS:Anal. Calcd. for [M+H]⁺ C₄₈H₅₁N₈O₆ 835.3932. found 835.3954

Example 123-125

Example 123-125 were prepared starting from boronate 1c and bromide 121cby using the methods described in Example 1, step d, Example 1, step e,and in the step describing the final preparation of Example 1.

    Example     Compound Name

RT (LC-Cond.); % homogeneity index; MS data 123(1R,1′R)-2,2′-((2-methyl- 4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)- 2,1- pyrrolidinediyl))bis(N,N- dimethyl-2-oxo-1-phenylethanamine)

1.12 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₇H₅₃N₈O₂: 761.43; found 761.49; HRMS: Anal. Calcd. for [M + H]⁺C₄₇H₅₃N₈O₂: 761.4291; found 761.4311 124 dimethyl ((2-methyl-4,4′-biphenyldiyl)bis(1H- imidazole-5,2-diyl(2S)- 2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate

1.34 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₇H₄₉N₈O₆: 821.38; found 821.45; HRMS: Anal. Calcd. for [M + H]⁺C₄₇H₄₉N₈O₆: 821.3775; found 821.3785 125 (1R,1′R)-2,2′-((2-methyl-4,4′-biphenyldiyl)bis(1H- imidazole-5,2-diyl(2S)- 2,1-pyrrolidinediyl))bis(2- oxo-1-phenylethanol)

1.23 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₆O₄: 707.34; found 707.38; HRMS: Anal. Calcd. for [M + H]⁺C₄₃H₄₃N₆O₄: 707.3346; found 707.3356

Examples 126-128

Example 126-128 were prepared starting from bromide 28b and boronate121d by using the methods described in Example 28 starting with step c.

    Example     Compound Name

RT (LC-Cond.); % homogeneity index; MS data 126 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2′- methyl-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.22 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₇H₅₁N₈O₄:791.40; found 791.70; HRMS: Anal. Calcd. for [M + H]⁺ C₄₇H₅₁N₈O₄:791.4033; found 791.4061 127 methyl ((1R)-2-((2S)-2-(5-(2′-methyl-4′-(2- ((2S)-1-(3- pyridinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.19 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₈O₄: 749.36; found 749.62; HRMS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₈O₄: 749.3564; found 749.3592 128 methyl ((1R)-2-((2S)-2-(5-(2′-methyl-4′-(2- ((2S)-1-((2S)- tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.27 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₇O₅: 728.36; found 728.59; HRMS: Anal. Calcd. for [M + H]⁺C₄₂H₄₆N₇O₅: 728.3560; found 728.3593

Example 129 methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2,2′-dimethyl-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Example 129 Step a

HATU (104.3 mg, 0.274 mmol) was added to a mixture of 121f, Cap-4 (58.8mg, 0.281 mmol) and diisopropylethylamine (110 μL, 0.631 mmol) in DMF(6.0 mL), and stirred for 90 minutes. The volatile component was removedin vacuo and the resulting crude material was purified by reverse phaseHPLC (H₂O/methanol/TFA), and free-based by MCX column (methanol wash;2.0 M NH₃/methanol) to provide 129a (89.9 mg). LC (Cond. 1): RT=1.22min; 95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₂N₇O₃644.34. found 644.55.

Example 129 methyl((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2,2′-dimethyl-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Example 129 (TFA salt) was prepared from 129a by the method used toconvert Example 1e to Example 1. LC (Cond. 1): RT=1.27 min; 97%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₈H₅₃N₈O₄ 805.42.found 805.61.

Example 130(1R,1′R)-2,2′-((2-(trifluoromethyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 130 Step a

Glyoxal (2.0 mL of 40% in water) was added dropwise over 11 minutes to amethanol solution of NH₄OH (32 mL) and (S)-Boc-prolinal (8.564 g, 42.98mmol) and stirred at ambient temperature for 19 hours. The volatilecomponent was removed in vacuo and the residue was purified by a flashchromatography (silica gel, ethyl acetate) followed by arecrystallization (ethyl acetate, room temperature) to provide imidazole130a as a white fluffy solid (4.43 g). ¹H NMR (DMSO-d₆, s=2.50, 400MHz): 11.68/11.59 (br s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76 (m, 1H),3.48 (m, 1H), 3.35-3.29 (m, 1H), 2.23-1.73 (m, 4H), 1.39/1.15 (s, 9H).LC (Cond. 1): RT=0.87 min; >95% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C₁₂H₂₀N₃O₂ 238.16. found 238.22. Imidazole 130a had an ee of98.9% when analyzed under chiral HPLC condition noted below.

Column: Chiralpak AD, 10 um, 4.6×50 mm

Solvent: 1.7% ethanol/heptane (isocratic)

Flow rate: 1 mL/min

Wavelength: either 220 or 256 nm

Relative retention time: 3.25 min (R), 5.78 minutes (S)

Example 130 Step b

N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in batches, over 15minutes, to a cooled (ice/water) CH₂Cl₂ (20 mL) solution of imidazole130a (1.0689 g, 4.504 mmol), and stirred at similar temperature for 75minutes. The volatile component was removed in vacuo. The crude materialwas purified by a reverse phase HPLC system (H₂O/methanol/TFA) toseparate bromide 130b from its dibromo-analog and the non-consumedstarting material. The HPLC elute was neutralized with excessNH₃/methanol and the volatile component was removed in vacuo. Theresidue was partitioned between CH₂Cl₂ and water, and the aqueous layerwas extracted with water. The combined organic phase was dried (MgSO₄),filtered, and concentrated in vacuo to provide 130b as a white solid(374 mg). ¹H NMR (DMSO-d₆, δ=2.50, 400 MHz): 12.12 (br s, 1H), 7.10 (m,1H), 4.70 (m, 1H), 3.31 (m, 1H; overlapped with water signal), 2.25-1.73(m, 4H), 1.39/1.17 (s, 3.8H+5.2H). LC (Cond. 1): RT=1.10 min; >95%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₉BrN₃O₂ 316.07.found 316.10.

Example 130 Step c

Pd(Ph₃P)₄ (78.5 mg, 0.0679 mmol) was added to a mixture of bromide 130b(545 mg, 1.724 mmol),2-(4-chloro-3-(trifluoromethyl)phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(542.8 mg, 1.771 mmol) (commercially available), NaHCO₃ (477 mg, 5.678mmol) in 1,2-dimethoxyethane (12.5 mL) and water (4.2 mL). The reactionmixture was purged with nitrogen, heated with an oil bath at 80° C. for27 hours, and then the volatile component was removed in vacuo. Theresidue was partitioned between CH₂Cl₂ and water, and the organic layerwas dried (MgSO₄), filtered, and concentrated in vacuo. The resultingcrude material was purified by a Biotage system (silica gel, 40-50%ethyl acetate/hexanes) followed by a reverse phase HPLC(water/methanol/TFA). The HPLC elute was treated with excessNH₃/methanol and concentrated. The residue was partitioned between waterand CH₂Cl₂, and the organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo to provide 130c as a white foam (317.4 mg). ¹H NMR(DMSO-d₆, δ=2.50, 400 MHz): 12.36/12.09/12.03 (br s, 1H), 8.15 (d,J=1.8, 0.93H), 8.09 (br s, 0.07H), 8.01 (dd, J=8.3/1.3, 0.93H), 7.93 (m,0.07H), 7.74 (m, 1H), 7.66 (d, J=8.3, 0.93H), 7.46 (m, 0.07H), 4.80 (m,1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.30-1.77 (m, 4 h), 1.40/1.15 (s,3.8H+5.2H). LC (Cond. 1): RT=1.52 min; >95% homogeneity index; LC/MS:Anal. Calcd. for [M+H]⁺ C₁₉H₂₂ClF₃N₃O₂ 416.14. found 416.17.

Example 130 Step d-e

Pd[P(t-Bu)₃]₂ (48 mg, 0.094 mmol) was added to a mixture of chloride130c (245 mg, 0.589 mmol), boronate 1c (277.1 mg, 0.631 mmol), KF (106.7mg, 1.836 mmol) in DMF (6 mL), and heated at 110° C. for ˜30 hours. Thevolatile component was removed in vacuo, and the residue was partitionedbetween CH₂Cl₂ (50 mL), water (20 mL) and saturated NaHCO₃ (1 mL). Theaqueous layer was extracted with CH₂Cl₂ (2×), and the combined organicphase was dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting material was purified by a Biotage system (silica gel, ethylacetate) to provide carbamate 130d as an off-white foam (297 mg). LC(Cond. 1): RT=1.44 min; >95% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺ C₃₇H₄₄F₃N₆O₄ 693.34. found 693.34.

The deprotection of 130d, which was conducted according to thepreparation of pyrrolidine 1e, provided 130e as a light yellow foam. ¹HNMR (DMSO-d₆, s=2.50, 400 MHz): 11.88 (br s, 2H), 8.16 (d, J=1.5, 1H),8.02 (d, J=7.8, 1H), 7.78 (d, J=8.1, 2H), 7.66 (br s, 1H), 7.48 (br s,1H), 7.37 (d, J=8.1, 1H), 7.28 (d, J=8.3, 2H), 4.18 (m, 2H), 2.99-2.93(m, 2H), 2.89-2.83 (m, 2H), 2.11-2.01 (m, 2H), 1.94-1.85 (m, 2H),1.82-1.67 (m, 4H). Note: although broad signals corresponding to thepyrrolidine NH appear in the 2.8-3.2 ppm region, the actual range fortheir chemical shift could not be determined. LC (Cond. 1): RT=1.12min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₇H₂₈F₃N₆493.23. found 493.14.

Example 130(1R,1′R)-2,2′-((2-(trifluoromethyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 130 (TFA salt) was prepared from 130e and Cap-1 according to thepreparation of Example 1 from pyrrolidine 1e. LC (Cond. 1): RT=1.17min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₇H₅₀F₃N₈O₂815.40. found 815.44; HRMS: Anal. Calcd. for [M+H]⁺ C₄₇H₅₀F₃N₈O₂815.4009. found 815.4013

Example 1315,5′-(2-(trifluoromethyl)-4,4′-biphenyldiyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazole)

Example 131 (TFA salt) was synthesized from 130e and Cap-5 according tothe preparation of Example 130.

LC (Cond. 1): RT=1.19 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₅₁H₅₄F₃N₈O₂ 867.43. found 867.51

HRMS: Anal. Calcd. for [M+H]⁺ C₅₁H₅₄F₃N₈O₂ 867.4322. found 867.4315

Example 131.1-1 to 131.1-2

Examples 131.1-1 through 131.1-2 were prepared in similar fashion toexample 28 via the intermediacy of intermediate 1-6e after appendingCap-4.

Example 131.1-1 methyl((1R)-2-(((1S)-1-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)ethyl)(methyl)amino)-2-oxo-1-phenylethyl)carbamate

Cap-1 was appended after the CBz carbamate was removed from 1-6e withPd/C/H₂.

LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10%water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. t_(R)=1.42min

LRMS: Anal. Calcd. for C₄₅H₄₉N₈O₄ 765.39. found: 765.38 (M+H)⁺.

HRMS: Anal. Calcd. for C₄₅H₄₉N₈O₄ Calcd 765.3877 found: 765.3905 (M+H)⁺.

Example 131.1-2 methyl((1R)-2-(methyl((1S)-1-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)ethyl)amino)-2-oxo-1-phenylethyl)carbamate

Cap-14 was appended after the CBz carbamate was removed from 1-6e withPd/C/H₂.

LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10%water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. t_(R)=1.45min (>95%)

LRMS: Anal. Calcd. for C₄₈H₅₂N₈O₄ 805.42. found: 805.41 (M+H)⁺.

HRMS: Anal. Calcd. C₄₈H₅₂N₈O₄ Calcd 805.4190 found: 805.4214 (M+H)⁺.

Example 131.2(2R)-2-(dimethylamino)-N-methyl-2-phenyl-N-((1S)-1-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)ethyl)acetamide

Example 131. 2 was prepared in similar fashion to example 131.1-1 andexample 131.1-2 via the intermediacy of intermediate 1-6e afterappending Cap-1. Cap-14 was appended after the CBz carbamate was removedwith Pd/C/H₂. LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100%B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1%TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.t_(R)=1.28 min

LRMS: Anal. Calcd. for C₄₈H₅₄N₈O₂ 775.44. found: 775.45 (M+H)⁺.

HRMS: Anal. Calcd. C₄₈H₅₄N₈O₂ Calcd 775.4448 found: 775.4460 (M+H)⁺.

Example 132(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

Example 132 Step a-b

A CH₂Cl₂ (10 mL) solution of Br₂ (7.63 g, 47.74 mmol) was added-dropwise over 5 min to a cooled (ice/water) CH₂Cl₂ (105 mL) solution of1-(6-bromopyridine-3-yl)ethanone (9.496 g, 47.47 mmol) and 48% HBr (0.4mL). The cooling bath was removed 40 min later, and stirring wascontinued at ambient temperature for about 66 hr. The cake of solid thatformed was filtered, washed with CH₂Cl₂ and dried in vacuo to affordimpure 132a as an off-white solid (15.94 g).

Boc-L-proline (9.70 g, 45.06 mmol) was added in one batch to aheterogeneous mixture of crude 132a (15.4 g) and CH₃CN (150 mL), andimmediately afterward Et₃N (13.0 mL, 93.2 mmol) was added drop-wise over6 min. The reaction mixture was stirred for 50 min, the volatilecomponent was removed in vacuo and the residue was partitioned betweenCH₂Cl₂ and water. The CH₂Cl₂ layer was dried (MgSO₄), filtered andconcentrated in vacuo, and the resultant material was purified by flashchromatography (silica gel; sample was loaded with eluting solvent; 25%EtOAc/hexanes) to afford 132b as a highly viscous yellow oil (11.44 g).¹H NMR (DMSO, δ=2.5 ppm; 400 MHz): 8.95 (m, 1H), 8.25-8.21 (m, 1H), 7.88(d, J=8.3, 1H), 5.65-5.46 (m, 2H), 4.36-4.31 (m, 1H), 3.41-3.29 (m, 2H),2.36-2.22 (m, 1H), 2.14-2.07 (m, 1H), 1.93-1.83 (m, 2H), 1.40 & 1.36(two s, 9H).

LC (Cond. 1): RT=2.01 min; >90% homogeneity index

LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₇H₂₁NaBrN₂O₅: 435.05. found 435.15

HRMS: Anal. Calcd. for [M+H]⁺ C₁₇H₂₂BrN₂O₅: 413.0712. found 413.0717

Example 132 Step c

A mixture of ketoester 132b (1.318 g, 3.19 mmol) and NH₄OAc (2.729 g,35.4 mmol) in xylenes (18 mL) was heated with a microwave at 140° C. for90 min. The volatile component was removed in vacuo and the residue waspartitioned between CH₂Cl₂ and water, where enough saturated NaHCO₃solution was added to neutralize the aqueous medium. The aqueous phasewas extracted with CH₂Cl₂, and the combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo. The resulting crudematerial was purified by a Biotage system (silica gel; 50%EtOAc/hexanes) to afford imidazole 132c as an off-white foam (1.025 g).¹H NMR (DMSO, δ=2.5 ppm, 400 MHz): 12.33/12.09/12.02 (br m, 1H), 8.74(d, J=2.3, 0.93H), 8.70 (app br s, 0.07H), 8.03/7.98 (dd for the firstpeak, J=8.3, 1H), 7.69/7.67 (br m, 1H), 7.58/7.43 (d for the first peak,J=8.3, 1H), 4.80 (m, 1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.33-2.11 (m, 1H),2.04-1.79 (m, 3H), 1.39/1.15 (app br s, 3.9H+5.1H).

LC (Cond. 1): RT=1.52 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₁₇H₂₂BrN₄O₂: 393.09. found 393.19

HRMS: Anal. Calcd. for [M+H]⁺ C₁₇H₂₂BrN₄O₂: 393.0926. found 393.0909

Example 132 Step d-e

Pd(Ph₃P)₄ (115.1 mg, 0.10 mmol) was added to a mixture of bromide 132c(992 mg, 2.52 mmol), boronate 1c (1.207 g, 2.747 mmol), NaHCO₃ (698.8mg, 8.318 mmol) in 1,2-dimethoxyethane (18 mL) and water (4 mL). Thereaction mixture was flushed with nitrogen, heated with an oil bath at90° C. for 37 hr and allowed to cool to ambient temperature. Thesuspension that formed was filtered and washed with water followed by1,2-dimethoxyethane, and dried in vacuo. A silica gel mesh was preparedfrom the crude solid and submitted to flash chromatography (silica gel;EtOAc) to afford carbamate 132d as a white solid, which yellowedslightly upon standing at ambient conditions (1.124 g). ¹H NMR indicatedthat the sample contains residual MeOH in a product/MeOH mole ratio of1.3.

LC (Cond. 1): RT=1.71 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃₅H₄₄N₇O₄: 626.35. found 626.64

HRMS: Anal. Calcd. for [M+H]⁺ C₃₅H₄₄N₇O₄: 626.3455; 626.3479

Carbamate 132d (217 mg) was treated with 25% TFA/CH₂Cl₂ (3.6 mL) andstirred at ambient condition for 6 hr. The volatile component wasremoved in vacuo, and the resultant material was free based by MCXcolumn (MeOH wash; 2.0 M NH₃/MeOH elution) to afford 132e as a dullyellow foam that solidified gradually upon standing (150.5 mg; mass isabove theoretical yield). ¹H NMR (DMSO, s=2.5 ppm; 400 MHz): 11.89 (verybroad, 2H), 9.01 (d, J=1.8, 1H), 8.13 (dd, J=8.3, 2.2, 1H), 8.07 (d,J=8.6, 2H), 7.92 (d, J=8.3, 1H), 7.83 (d, J=8.5, 2H), 7.61 (br s, 1H),7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.93 (m, 2H), 2.90-2.82 (m, 2H),2.11-2.02 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.67 (m, 4H). [Note: theexchangeable pyrrolidine hydrogens were not observed]

LC (Cond. 1): RT=1.21 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₅H₂₈N₇: 426.24. found 426.40

HRMS: Anal. Calcd. for [M+H]⁺ C₂₅H₂₈N₇: 426.2406. found 426.2425

Example 132(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

HATU (41.4 mg, 0.109 mmol) was added to a mixture of pyrrolidine 132e(23.1 mg, 0.054 mmol), (i-Pr)₂EtN (40 μL, 0.23 mmol) and Cap-1 (25.3 mg,0.117 mmol) in DMF (1.5 mL), and the mixture was stirred at ambient for1 hr. The volatile component was removed in vacuo, and the residue waspurified first by MCX (MeOH wash; 2.0 M NH₃/MeOH elution) and then by areverse phase HPLC (H₂O/MeOH/TFA) to afford the TFA salt of Example 132as a yellow foam (39.2 mg).

LC (Cond. 1): RT=1.37 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₅H₅₀N₉O₂: 748.41. found 748.53

HRMS: Anal. Calcd. for [M+H]⁺ C₄₅H₅₀N₉O₂: 748.4087. found 748.4090

Example 133-135 were prepared as TFA salts from 132e by using the samemethod of preparations as Example 132 and appropriate reagents.

Example 133-135

    Example     Compound Name

RT (LC-Cond.); % homogeneity index; MS data 133(1R)-2-((2S)-2-(5-(6-(4-(2- ((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethanol

1.49 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₀N₇O₄:694.31; found 694.42 HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₀N₇O₄:694.3142, found: 694.3164 134 methyl ((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.60 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₆N₉O₆:808.36; found 808.51 HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₆N₉O₆:808.3571; found 808.3576 135 5-(2-((2S)-1-((2R)-2-methoxy-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2-(4-(2-((2S)-1-((2R)-2- methoxy-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)phenyl)pyridine

1.60 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₄N₇O₄:722.35; found 722.40 HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₄N₇O₄:722.3455; found 722.3464

Example 136(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

Example 136 Step a and b

PdCl₂(Ph₃P)₂ (257 mg, 0.367 mmol) was added to a dioxane (45 mL)solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) andtri-n-butyl(1-ethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at80° C. for 17 hr. The reaction mixture was treated with water (15 mL),cooled to ˜0° C. (ice/water), and then NBS (1.839 g, 10.3 mmol) wasadded in batches over 7 min. About 25 min of stirring, the volatilecomponent was removed in vacuo, and the residue was partitioned betweenCH₂Cl₂ and water. The aqueous layer was extracted with CH₂Cl₂, and thecombined organic phase was dried (MgSO₄), filtered, and concentrated invacuo. The resulting crude material was purified by a gravitychromatography (silica gel; 4% EtOAc/hexanes) to afford bromide 136a asa brownish-yellow solid (2.699 g); the sample is impure and containsstannane-derived impurities, among others. ¹H NMR (CDCl₃, δ=7.24, 400MHz): 7.83 (s, 1H), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

An CH₃CN (15 mL) solution of 136a (2.69 g, <9.21 mmol) was added dropwise over 3 min to a CH₃CN (30 mL) solution of (S)-Boc-proline (2.215 g,10.3 mmol) and Et₃N (1.40 mL, 10.04 mmol), and stirred for 90 min. Thevolatile component was removed in vacuo, and the residue was partitionedbetween water and CH₂Cl₂, and the organic phase was dried (MgSO₄),filtered, and concentrated in vacuo. The resultant crude material waspurified by a flash chromatography (silica gel; 15-20% EtOAc/hexanes) toafford 136b as a colorless viscous oil (2.74 g). ¹H NMR (DMSO-d₆,δ=2.50, 400 MHz): 7.98 (m, 1H), 7.78 (d, J=8.3, 1H), 7.72-7.69 (m, 1H),5.61-5.41 (m, 2H), 4.35-4.30 (m, 1H), 3.41-3.30 (m, 2H), 2.43 (s, 3H),2.33-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36 (s, 9H).

LC (Cond. 1): RT=1.91 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₉H₂₄BrNNaO₅ 448.07. found 448.10

Example 136 Step c

A mixture of ketoester 136b (1.445 g, 3.39 mmol) and NH₄OAc (2.93 g,38.0 mmol) in xylenes (18 mL) was heated with a microwave at 140° C. for80 min. The volatile component was removed in vacuo, and the residue wascarefully partitioned between CH₂Cl₂ and water, where enough saturatedNaHCO₃ solution was added to neutralize the aqueous medium. The aqueousphase was extracted with CH₂Cl₂, and the combined organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo. The crude waspurified by a flash chromatography (silica gel, 40% EtOAc/hexanes) toafford imidazole 136c as an off-white solid (1.087 g). ¹H NMR (DMSO-d₆,δ=2.50, 400 MHz): 12.15/11.91/11.84 (br s, 1H), 7.72-7.24 (m, 4H), 4.78(m, 1H), 3.52 (m, 1H), 3.38-3.32 (m, 1H), 2.35 (s, 3H), 2.28-1.77 (m,4H), 1.40/1.14 (s, 9H).

LC (Cond. 1): RT=1.91 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₁₉H₂₅BrN₃O₂ 405.96. found 406.11

Example 136 Step d

PdCl₂dppf.CH₂Cl₂ (50.1 mg, 0.061 mmol) was added to a pressure tubecontaining a mixture of bromide 136c (538.3 mg, 1.325 mmol),bis(pinacolato)diboron (666.6 mg, 2.625 mmol), KOAc (365.8 mg, 3.727mmol) and DMF (10 mL). The reaction mixture was flushed with N₂ andheated at 80° C. for 24.5 hr. The volatile component was removed invacuo and the residue was partitioned between CH₂Cl₂ and water, whereenough saturated NaHCO₃ solution was added to make the pH of the aqueousmedium neutral. The aqueous phase was extracted with CH₂Cl₂, and thecombined organic phase was dried (MgSO₄), filtered, and concentrated invacuo. The resulting material was purified by a Biotage system (silicagel, 40-50% EtOAc/hexanes) to afford boronate 136d as a white foam (580mg). According to ¹H NMR the sample contains residual pinacol in aproduct/pinacol ratio of ˜3. ¹H NMR (DMSO-d₆, δ=2.50, 400 MHz):12.16/11.91/11.83 (br s, 1H), 7.63-7.25 (m, 4H), 4.78 (m, 1H), 3.53 (m,1H), 3.39-3.32 (m, 1H), 2.48/2.47 (s, 3H), 2.28-1.78 (m, 4H),1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H).

LC (Cond. 1): RT=1.62 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₅H₃₇BN₃O₄ 454.29. found 454.15

Example 136 Step e-f

Biaryl 136e was prepared from bromide 132c and boronate 136d accordingto the coupling condition described for the preparation of biaryl 132d.

LC (Cond. 1a): RT=1.32 min; >90% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃₆H₄₅N₇O₄ 640.36. found 640.66

The deprotection of biaryl 136e was done according to the preparation ofpyrrolidine 132e to afford 136f as a light yellow foam. ¹H NMR (DMSO-d₆,δ=2.50, 400 MHz): 11.88 (br s, 2H), 9.02 (d, J=2, 1H), 8.12 (dd, J=8.4,2.3, 1H), 7.67 (s, 1H), 7.64-7.62 (m, 2H), 7.50 (d, J=8.3, 1H), 7.46 (brs, 1H), 7.40 (d, J=7.8, 1H), 4.21-4.14 (m, 2H), 3.00-2.93 (m, 2H),2.90-2.82 (m, 2H), 2.40 (s, 3H), 2.11-2.01 (m, 2H), 1.94-1.85 (m, 2H),1.82-1.66 (m, 4H). [Note: the signal for the pyrrolidine NH appears inthe region 3.22-2.80 and is too broad to make a chemical shiftassignment.]

LC (Cond. 1): RT=0.84 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₆H₃₀N₇ 440.26. found 440.50

Example 136(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

Example 136 (TFA salt) was synthesized from 136f according to thepreparation of Example 132 from 132e.

1.05 min (Cond. 1); >98%

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₆H₅₂N₉O₂: 762.42. found: 762.77

HRMS: Anal. Calcd. for [M+H]⁺ C₄₆H₅₂N₉O₂: 762.4244. found 762.4243

Example 138 methyl((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Example 138 was prepared similarly from pyrrolidine 136f and Cap-4.

1.60 min (Cond. 1); >98%

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₆H₄₈N₉O₆: 822.37. found 822.74

HRMS: Anal. Calcd. for [M+H]⁺ C₄₆H₄₈N₉O₆: 822.3728. found 822.3760

Example 139N-((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)acetamide

Example 139 Step a

HATU (99.8 mg, 0.262 mmol) was added to a mixture of 132e (54.1 mg,0.127 mmol), (R)-2-(t-butoxycarbonylamino)-2-phenylacetic acid (98.5 mg,0.392 mmol) and i-Pr₂EtN (100 μL, 0.574 mol), and the reaction mixturewas stirred for 70 min. The volatile component was removed in vacuo, andthe residue was purified by a reverse phase HPLC (H₂O/MeOH/TFA), wherethe HPLC elute was treated with excess 2.0 N NH₃/MeOH before the removalof the volatile component in vacuo. The resulting material waspartitioned between CH₂Cl₂ and water, and the aqueous phase wasextracted with CH₂Cl₂ (2×). The combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo. Carbamate 139a wasobtained as a white film of foam (82.3 mg).

LC (Cond. 1): RT=1.97 min; >95% homogeneity index.

LC/MS: Anal. Calcd. for [M+H]⁺ C₅₁H₅₈N₉O₆: 892.45. found 892.72

Example 139b Step b

Carbamate 139a was deprotected to amine 139b by using the proceduredescribed for the preparation of pyrrolidine 132e from 132d.

LC (Cond. 1): RT=1.37 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₁H₄₂N₉O₂: 692.35. found 692.32

Example 139N-((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)acetamide

Acetic anhydride (20 μL, 0.212 mmol) was added to a DMF (1.5 mL)solution of 139b (31.2 mg, 0.045 mmol), and the reaction mixture wasstirred for 1 hr. NH₃/MeOH (1.0 mL of 2N) was added to the reactionmixture and stirring continued for 100 min. The volatile component wasremoved in vacuo and the resulting crude material was purified by areverse phase HPLC (H₂O/MeOH/TFA) to afford the TFA salt of Example 139as a light yellow solid (24.1 mg).

LC (Cond. 1): RT=1.53 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₅H₄₆N₉O₄: 776.37. found 776.38

HRMS: Anal. Calcd. for [M+H]⁺ C₄₅H₄₆N₉O₄: 776.3673. found 776.3680

Example 140 methyl((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Example 140 Step a

HATU (19.868 g, 52.25 mmol) was added to a heterogeneous mixture ofN-Cbz-L-proline (12.436 g, 49.89 mmol) and the HCl salt of2-amino-1-(4-bromophenyl)ethanone (12.157 g, 48.53 mmol) in DMF (156mL). The mixture was lowered in an ice-water bath, and immediatelyafterward N,N-diisopropylethylamine (27 mL, 155 mmol) was added dropwise to it over 13 min. After the addition of the base was completed,the cooling bath was removed and the reaction mixture was stirred for anadditional 50 min. The volatile component was removed in vacuo; water(125 mL) was added to the resultant crude solid and stirred for about 1hr. The off-white solid was filtered and washed with copious water, anddried in vacuo to afford ketoamide 140a as a white solid (20.68 g). ¹HNMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 8.30 (m, 1H), 7.91 (m, 2H), 7.75 (d,J=8.5, 2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H), 4.57-4.48 (m, 2H),4.33-4.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.94-1.78 (m,3H).

LC (Cond. 1): RT=1.65 min; 98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₁H₂₂BrN₂O₄: 445.08. found 445.31

Example 140 Step b

Ketoamide 140a (10.723 g, 24.08 mmol) was converted to 140b according tothe procedure described for the synthesis of carbamate 132c, with theexception that the crude material was purified by flash chromatography(silica gel; 50% EtOAc/hexanes). Bromide 140b was retrieved as anoff-white foam (7.622 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz):12.23/12.04/11.97 (m, 1H), 7.73-6.96 (m, 10H), 5.11-4.85 (m, 3H), 3.61(m, 1H), 3.45 (m, 1H), 2.33-184 (m, 4H).

LC (Cond. 1): RT=1.42 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₁H₂₁BrN₃O₂: 426.08. found 426.31

HRMS: Anal. Calcd. for [M+H]⁺ C₂₁H₂₁BrN₃O₂: 426.0817. found: 426.0829

The optical purity of 140b was assessed using the following chiral HPLCmethods, and an ee of 99% was observed.

Column: Chiralpak AD, 10 um, 4.6×50 mm

Solvent: 20% ethanol/heptane (isocratic)

Flow rate: 1 ml/min

Wavelength: 254 nm

Relative retention time: 1.82 min (R), 5.23 min (S)

Example 140 Step c

Pd(Ph₃P)₄ (208 mg, 0.180 mmol) was added to a pressure tube containing amixture of bromide 140b (1.80 g, 4.22 mmol), bis(pinacolato)diboron(2.146 g, 8.45 mmol), KOAc (1.8 g, 11.0 mmol) and 1,4-dioxane (34 mL).The reaction flask was purged with nitrogen, capped and heated with anoil bath at 80° C. for 23 hr. The volatile component was removed invacuo, and the residue was partitioned carefully between CH₂Cl₂ (70 mL)and an aqueous medium (22 mL water+5 mL saturated NaHCO₃ solution). Theaqueous layer was extracted with CH₂Cl₂, and the combined organic phasewas dried (MgSO₄), filtered, and concentrated in vacuo. The oily residewas crystallized from EtOAc/hexanes to afford two crops of boronate 140cas a yellow solid (1.52 g). The mother liquor was evaporated in vacuoand the resulting material was purified by flash chromatography (silicagel; 20-35% EtOAc/CH₂Cl₂) to afford additional 140c as an off-whitesolid, containing residual pinacol (772 mg).

LC (Cond. 1): RT=1.95 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₇H₃₃BN₃O₄: 474.26. found 474.31

Example 140 Step d-e

Arylbromide 132c was coupled with boronate 140c to afford 140d by usingthe same procedure described for the synthesis of biaryl 132d. Thesample contains the desbromo version of 132c as an impurity. Proceededto the next step without further purification.

LC (Cond. 1): RT=1.72 min; ˜85% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₂N₇O₄: 660.33. found 660.30

A mixture of 10% Pd/C (226 mg), biaryl 140d (1.25 g) and MeOH (15 mL)was stirred under a balloon of hydrogen for ˜160 hr, where the hydrogensupply was replenished periodically as needed. The reaction mixture wasfiltered through a pad of diatomaceous earth (Celite®), and the filtratewas evaporated in vacuo to afford crude 140e as a yellowish-brown foam(911 mg). Proceeded to the next step without further purification.

LC (Cond. 1): RT=1.53 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₃₀H₃₆N₇O₂: 526.29. found 526.23

Example 140 Step f-g

Pyrrolidine 140g was prepared from 140e and Cap-4, via the intermediacyof carbamate 140f, by sequentially employing the amide forming andBoc-deprotection protocols used in the synthesis of Example 132.

LC (Cond. 1): RT=1.09 min; ˜94% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃₅H₃₇N₈O₃: 617.30. found 617.38

Example 140 methyl((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

The TFA salt of Example 140 was synthesized from pyrrolidine 140g andCap-1 by using the procedure described for the preparation of Example132 from intermediate 132e.

1.15 min (Cond. 1); >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₅H₄₀N₇O₄: 778.38. found 778.48

HRMS: Anal. Calcd. for [M+H]⁺ C₄₅H₄₀N₇O₄: 778.3829. found 778.3849

The TFA salt of Example 141-143 were synthesized from intermediate 140gand appropriate reagents in a similar manner.

Example 141-143

    Example     Compound Name

RT (LC-Cond.); % homogeneity index; MS data 141 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4-(5- (2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

1.15 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₃N₈O₅:715.34; found 715.44 HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₃N₈O₅:715.3356; found 715.3381 142 methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-((1-methyl- 4-piperidinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.07 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₈N₉O₄:742.38; found 742.48 HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₈N₉O₄:742.3829; found 742.3859 143 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4-(5- (2-((2S)-1-(3- pyridinylacetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate

1.09 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₂N₉O₄:736.34; found 736.44 HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₂N₉O₄:736.3360; 736.3344

Example 144 methyl((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-(4-morpholinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

A DMF (1.5 mL) solution of morpholine-4-carbonyl chloride (8.5 mg, 0.057mmol) was added to a mixture of i-Pr₂EtN (20 μL, 0.115 mmol) and 140g(27.3 mg, 0.044 mmol), and stirred for 100 min. The volatile componentwas removed in vacuo and the residue was purified by a reverse phaseHPLC (H₂O/MeOH/TFA) to afford the TFA salt of Example 144 as a yellowfoam (34.6 mg).

1.17 min (Cond. 1); >98%

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₀H₄₄N₉O₅: 730.35. found 730.42

HRMS: Anal. Calcd. for [M+H]⁺ C₄₀H₄₄N₉O₅: 730.3465. found 730.3477

Example 145 dimethyl(2,2′-bipyridine-5,5′-diylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

Example 145 Step a-b

Pd(Ph₃P)₄ (9.6 mg, 0.008 mmol) and LiCl (28 mg, 0.67 mmol) were added toa mixture of arylbromide 132c (98.7 mg, 0.251 mmol) and hexamethylditin(51.6 mg, 0.158 mmol), and heated at 80° C. for ˜3 days. The volatilecomponent was removed in vacuo and the resultant crude material waspurified by flash chromatography (silica gel; 0-10% MeOH/EtOAc) followedby a reverse phase HPLC (H₂O/MeOH/TFA). The HPLC elute was neutralizedwith excess 2.0 N NH₃/MeOH, and the volatile component was removed invacuo. The residue was partitioned between CH₂Cl₂ and water, and theaqueous phase was washed with CH₂Cl₂ (2×).

The combined organic phase was dried (MgSO₄), filtered, and concentratedin vacuo to afford carbamate 145a as a film of oil (8.7 mg).

LC (Cond. 1): RT=1.68 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃₄H₄₃N₈O₄: 627.34. found 627.47

Carbamate 145a was elaborated to pyrrolidine 145b according to thepreparation of 132e from 132d. ¹H NMR (DMSO, s=2.5 ppm; 400 MHz): 12.02(br signal, 2H), 9.04 (d, J=1.6, 2H), 8.34 (d, J=8.3, 2H), 8.20 (dd,J=8.3, 2.3, 2H), 7.67 (br s, 1H), 4.21 (m, 2H), 3.00-2.85 (m, 4H),2.12-2.04 (m, 2H), 1.95-1.68 (m, 6H). [Note: the pyrrolidine-NH signalwas not observed].

LC (Cond. 1): RT=1.17 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₄H₂₇N₈: 427.24. found 427.13

Example 145 dimethyl(2,2′-bipyridine-5,5′-diylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

Example 145 (TFA salt) was synthesized from 145b according to thepreparation of Example 132 from 132e.

LC (Cond. 1): RT=1.63 min; 98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₄H₄₅N₁₀O₆: 809.35. found 809.40

Example 146(1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

Example 146 Step a

n-BuLi (12.0 mL of 2.5M/hexanes, 30 mmol) was added drop-wise over 15min to a cooled (−78° C.) toluene (300 mL) semi-solution of2,5-dibromopyridine (6.040 g, 25.5 mmol), and stirred for 2.5 hr.t-Butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (2.809 g, 12.87mmol) was added in batches over 7 min, and stirring continued for 1.5 hrat −78° C. The −78° C. bath was replaced with −60° C. bath, which wasallowed to warm up to −15° C. over 2.5 hr. The reaction was quenchedwith saturated NH₄Cl solution (20 mL), and the mixture was allowed tothaw to ambient temperature and the organic layer was separated andevaporated in vacuo. The resulting crude material was purified by flashchromatography (silica gel; 15% EtOAc/hexanes) to afford a reddish brownsemisolid, which was washed with hexanes to removed the colored residue.Pyridine 146a was retrieved as an ash colored solid (842 mg). ¹H NMR(DMSO, δ=2.5 ppm; 400 MHz): 8.89 (d, J=2.3, 1H), 8.30 (dd, J=8.4, 2.4,1H), 7.90 (d, J=8.3, 1H), 7.03 (br t, J=5.7; 0.88H), 6.63 (app br s,0.12H), 4.55 (d, J=5.8, 2H), 1.40/1.28 (two app s, 7.83H+1.17H).

LC (Cond. 1): RT=2.00 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₂H₁₅BrNaN₂O₃: 337.02. found 337.13

Example 146 Step b

48% HBr (1.0 mL) was added drop-wise to a dioxane (5.0 mL) solution ofcarbamate 146a (840 mg, 2.66 mmol) over 3 min, and the reaction mixturewas stirred at ambient temperature for 17.5 hr. The precipitate wasfiltered and washed with dioxane, and dried in vacuo to afford amine theHBr salt of 146b as an off-white solid (672.4 mg; the exact moleequivalent of the HBr salt was not determined). ¹H NMR (DMSO, δ=2.5 ppm;400 MHz): 8.95 (d, J=2.3, 1H), 8.37 (dd, J=8.4, 2.3, 1H), 8.2 (br s,3H), 8.00 (d, J=8.3, 1H), 4.61 (s, 2H).

LC (Cond. 1): RT=0.53 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₇H₈BrN₂O: 214.98. found 215.00

Example 146 Step c

i-Pr₂EtN (2.3 mL, 13.2 mmol) was added drop-wise over 15 min to aheterogeneous mixture of amine 146b (1.365 g), (S)-Boc-proline (0.957 g,4.44 mmol) and HATU (1.70 g, 4.47 mmol) in DMF (13.5 mL), and stirred atambient temperature for 1 hr. The volatile component was removed invacuo and the residue was partitioned between EtOAc (40 mL) and anaqueous medium (20 mL water+1 ml saturated NaHCO₃ solution). The aqueouslayer was washed with EtOAc (20 mL), and the combined organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultant crudematerial was purified by flash chromatography (silica gel; 40-50%EtOAc/hexanes) to afford ketoamide 146c as a faint-yellow foam (1.465g). ¹H NMR (DMSO, δ=2.5 ppm; 400 MHz): 8.90 (d, J=2.3, 1H), 8.30 (dd,J=8.5, 2.4, 1H), 8.01-8.07 (m, 1H), 7.90 (d, J=8.3, 1H), 4.6 (m, 1H),4.64 (dd, J=19.1, 5.5, 1H); 4.19 (m, 1H), 3.39 (m, 1H), 3.32-3.26 (m,1H), 2.20-2.01 (m, 1H), 1.95-1.70 (m, 3H), 1.40/1.35 (two app s, 9H).

LC (Cond. 1): RT=1.91 min

LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₇H₂₂BrN₃NaO₄: 434.07. found 433.96.

Example 146 Step d

A mixture of ketoamide 146c (782.2 mg, 1.897 mmol) and NH₄OAc (800 mg,10.4 mmol) in xylenes was heated with a microwave (140° C.) for 90 min.The volatile component was removed in vacuo and the residue wascarefully partitioned between CH₂Cl₂ and water, where enough saturatedNaHCO₃ solution was added to neutralize it. The aqueous phase wasextracted with CH₂Cl₂ (2×), and the combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo. The resultant crudematerial was purified by flash chromatography (silica gel; 50%CH₂Cl₂/EtOAc) to afford imidazole 146d as an off-white solid (552.8 mg).¹H NMR (DMSO, δ=2.5 ppm; 400 MHz): 12.49/12.39/12.15/12.06 (br s, 1H),8.62 (app br s, 0.2H), 8.56 (d, J=2, 0.8H), 8.02 (br d, J=8.5, 0.2H),7.97 (br d, J=7.8, 0.8H), 7.77 (d, J=8.6, 0.8H), 7.72 (d, J=8.6, 0.2H),7.61-7.49 (m, 1H), 4.93-4.72 (m, 1H), 3.53 (m, 1H), 3.41-3.32 (m, 1H),2.33-1.77 (m, 4H), 1.39/1.14 (app br s, 3.7H+5.3H).

LC (Cond. 1): RT=1.67 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₇H₂₁BrN₄NaO₂: 415.08. found 415.12

Example 146 Step e

NaH (60%; 11.6 mg, 0.29 mmol) was added in one batch to a heterogeneousmixture of imidazole 146d (80 mg, 0.203 mmol) and DMF (1.5 mL), andstirred at ambient condition for 30 min. SEM-Cl (40 μL, 0.226 mmol) wasadded drop-wise over 2 min to the above reaction mixture, and stirringwas continued for 14 hr. The volatile component was removed in vacuo andthe residue was partitioned between water and CH₂Cl₂. The aqueous layerwas extracted with CH₂Cl₂, and the combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo. The crude material waspurified by a flash chromatography (silica gel; 20% EtOAc/hexanes) toafford 146e as a colorless viscous oil (87.5 mg). The exactregiochemistry of 146e was not determined. ¹H NMR (CDCl₃, δ=7.4 ppm; 400MHz): 8.53 (d, J=2.2, 1H), 7.90-7.72 (m, 2H), 7.52 (s, 1H), 5.87 (m,0.46H), 5.41 (m, 0.54H), 5.16 (d, J=10.8, 1H), 5.03-4.85 (m, 1H),3.76-3.42 (m, 4H), 2.54-1.84 (m, 4H), 1.38/1.19 (br s, 4.3H+4.7H),0.97-0.81 (m, 2H), −0.03 (s, 9H).

LC (Cond. 1): RT=2.1 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₃H₃₆BrN₄O₃Si: 523.17. found 523.24

Example 146 Step f

Pd(Ph₃P)₄ (24.4 mg, 0.021 mmol) was added to a mixture of imidazole 146e(280 mg, 0.535 mmol), 1c (241.5 mg, 0.55 mmol) and NaHCO₃ (148.6 mg,1.769 mmol) in 1,2-dimethoxyethane (4.8 mL) and water (1.6 mL). Thereaction mixture was flushed with nitrogen, heated with an oil bath at80° C. for ˜24 hr and then the volatile component was removed in vacuo.The residue was partitioned between CH₂Cl₂ and water, and the organicphase was dried (MgSO₄), filtered, and concentrated in vacuo. The crudematerial was purified by a Biotage system (silica gel; 75-100%EtOAc/hexanes) followed by a reverse phase HPLC (H₂O/MeOH/TFA). The HPLCelute was neutralized with 2M NH₃/MeOH and evaporated in vacuo, and theresidue was partitioned between water and CH₂Cl₂. The organic layer wasdried (MgSO₄), filtered, and concentrated in vacuo to afford 146f as awhite foam (162 mg).

LC (Cond. 1): RT=2.1 min

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₈N₇O₅Si: 756.43. found 756.55

Example 146 Step g

Carbamate 146f (208 mg, 0.275 mmol) was treated with 25% TFA/CH₂Cl₂ (4.0mL) and stirred at ambient temperature for 10 hr. The volatile componentwas removed in vacuo and the residue was first free-based by MCX (MeOHwash; 2.0 M NH₃/MeOH elution) and then purified by a reverse phase HPLC(H₂O/MeOH/TFA), and the resultant material was free-based again (MCX) toafford pyrrolidine 146g as a film of oil (53.7 mg). ¹H NMR (DMSO, δ=2.5ppm; 400 MHz): 1.88 (app br s, 2H), 8.83 (d, J=2.1, 1H), 8.07 (dd,J=8.3/2.3, 1H0, 7.87 (d, J=8.5, 1H), 7.84 (d, J=8.3, 2H), 7.71 (d,J=8.3, 2H), 7.55 (s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.94 (m,2H), 2.89-2.83 (m, 2H), 2.11-2.02 (m, 2H), 1.95-1.86 (m, 2H), 1.83-1.67(m, 4H).

LC (Cond. 1): RT=0.95 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₅H₂₈N₇: 426.24. found 426.27

Example 146(1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

Example 146 (TFA salt) was synthesized from pyrrolidine 146g accordingto the preparation of Example 132 from intermediate 132e.

LC (Cond. 1): RT=1.42 min; 96.5% homogenity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₅H₅₀N₉O₂: 748.41. found 748.57

HRMS: Anal. Calcd. for [M+H]⁺ C₄₅H₅₀N₉O₂: 748.4087. found 748.4100

Example 147 methyl((1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

The TFA salt of Example 147 was prepared similarly from intermediate146g by using Cap-4.

LC (Cond. 1): RT=1.66 min; 95% homogenity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄₅H₄₆N₉O₆: 808.36. found 808.55

Example 148(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(4R)-1,3-thiazolidine-4,3-diyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 148 Step a

A solution of bromine (1.3 mL, 25.0 mmol) in 15 mL glacial acetic acidwas added drop-wise to a solution of 4-4′-diacetylbiphenyl (3.0 g, 12.5mmol) in 40 mL acetic acid at 50° C. Upon completion of addition themixture was stirred at room temperature overnight. The precipitatedproduct was filtered off and re-crystallized from chloroform to give1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) (3.84 g, 77.5%) as a whitesolid.

¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.09 (4H, d, J=7.93 Hz) 7.75 (4H,d, J=8.24 Hz) 4.47 (4H, s)

Nominal/LRMS—Anal. Calcd. for 369.07 found; (M+H)⁺—397.33, (M−H)⁻-395.14

Example 148 Step b

Sodium diformylamide (3.66 g, 38.5 mmol) was added to a suspension of1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) (6.1 g, 15.4 mmol) in 85mL acetonitrile. The mixture was heated at reflux for 4 hours andconcentrated under reduced pressure. The residue was suspended in 300 mL5% HCl in ethanol and heated at reflux for 3.5 hours. Reaction wascooled to room temperature and placed in the freezer for 1 hour.Precipitated solid was collected, washed with 200 mL 1:1 ethanol/etherfollowed by 200 mL pentane, and dried under vacuum to give1,1′-(biphenyl-4,4′-diyl)bis(2-aminoethanone) dihydrochloride (4.85 g,92%). Carried on without further purification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.47-8.55 (4H, m) 8.11-8.17 (4H, m) 8.00(4H, d, J=8.42 Hz) 4.59-4.67 (4H, m).

LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10%water 0.1% TFA, t_(R)=0.44 minutes, Anal. Calcd. for C₁₆H₁₆N₂O₂ 268.31found; 269.09 (M+H)⁺.

Example 148 Step c

To a stirred solution of 1,1′-(biphenyl-4,4′-diyl)bis(2-aminoethanone)dihydrochloride (0.7 g, 2.1 mmol), N-(tert-butoxycarbonyl)-L-thioproline (0.96 g, 4.2 mmol), and HATU (1.68 g, 4.4 mmol)in 14 mL DMF was added diisopropylethyl amine (1.5 mL, 8.4 mmol)drop-wise over 5 minutes. The resulting clear yellow solution wasstirred at room temperature overnight (14 hours) and concentrated underreduced pressure. The residue was partitioned between 20%methanol/chloroform and water. The aqueous phase was washed once with20% methanol/chloroform. The combined organics were washed with brine,dried (MgSO₄), filtered, and concentrated under reduced pressure. Thecrude product was chromatographed on silica gel by gradient elution with10-50% ethyl acetate/CH₂Cl₂ to give (4S,4′S)-tert-butyl4,4′-(2,2′-(biphenyl-4,4′-diyl)bis(2-oxoethane-2,1-diyl))bis(azanediyl)bis(oxomethylene)dithiazolidine-3-carboxylate(0.39 g, 27%) as an orange foam.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.38 (2H, s) 8.12 (4H, d, J=8.56 Hz)7.94 (4H, d, J=8.56 Hz) 4.60-4.68 (4H, m) 4.33-4.38 (2H, m) 3.58-3.68(2H, m) 3.38 (2H, s) 3.08-3.18 (2H, m) 1.40 (18H, s)

LCMS—Water-Sunfire C-18 4.6×50 mm, 0 to 100% B over 4.0 minute gradient,1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol10% water 0.1% TFA, t_(R)=3.69 min., Anal. Calcd. for C₃₄H₄₂N₄O₈S₂698.85 found; 699.12 (M+H)⁺.

Example 148 Step d

(4S,4′S)-tert-butyl4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dithiazolidine-3-carboxylate(0.39 g, 0.56 mmol) and ammonium acetate (0.43 g, 5.6 mmol) weresuspended in 8 mL o-xylene in a microwave reaction vessel. The mixturewas heated under standard microwave conditions at 140° C. for 70 minutesand concentrated under reduced pressure. The residue was dissolved in 30mL 20% methanol/chloroform and washed with 10% NaHCO₃(aq). The organiclayer was washed with brine, dried (MgSO₄), filtered, and concentratedunder reduced pressure. The crude product was chromatographed on silicagel by gradient elution with 1-6% methanol/CH₂Cl₂ to give(4S,4′S)-tert-butyl4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dithiazolidine-3-carboxylate(0.15 g, 41%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.02 (2H, s) 7.70-7.88 (10H, m)5.28-5.37 (2H, m) 4.68 (2H, d, J=9.16 Hz) 4.47-4.55 (2H, m) 3.46 (2H, s)3.23 (2H, s) 1.26-1.43 (18H, m)

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 3.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=1.96 min., Anal.Calcd. for C₃₄H₄₀N₆O₄S₂ 660.85 found; 661.30 (M+H)⁺, 659.34 (M−H)⁻

Example 148 Step e

To a solution of (4S,4′S)-tert-butyl4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dithiazolidine-3-carboxylatein 1 mL dioxane was added 0.3 mL of a 4.0M solution of HCl in dioxane.The reaction was stirred for 3 hours at room temperature andconcentrated under reduced pressure. The resulting tan solid was driedunder vacuum to give4,4′-bis(2-((S)-thiazolidin-4-yl)-1H-imidazol-5-yl)biphenyltetrahydrochloride (0.12 g, 100%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.09 (2H, s) 8.01 (4H, d, J=8.55 Hz)7.90 (4H, d, J=8.55 Hz) 5.08 (2H, t, J=6.10 Hz) 4.38 (2H, d, J=9.16 Hz)4.23 (2H, d, J=9.46 Hz) 3.48-3.54 (2H, m,) 3.35-3.41 (2H, m)

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=1.70 min., Anal.Calcd. for C₂₄H₂₄N₆S₂ 460.62 found; 461.16 (M+H)⁺, 459.31 (M−H)⁻

Example 148(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(4R)-1,3-thiazolidine-4,3-diyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

To a stirred solution of(4,4′-bis(2-((S)-thiazolidin-4-yl)-1H-imidazol-5-yl)biphenyltetrahydrochloride (0.028 g, 0.046 mmol),(R)-2-(dimethylamino)-2-phenylacetic acid (Cap-1, 0.017 g, 0.0.10 mmol),and HATU (0.039 g, 0.10 mmol) in 2 mL DMF was added diisopropylethylamine (0.05 mL, 0.28 mmol). The reaction was stirred at room temperatureovernight (16 hours) and concentrated under reduced pressure. The crudeproduct was purified by reverse-phase preparative HPLC to provide(2R,2′R)-1,1′-((4S,4′S)-4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(thiazolidine-4,3-diyl))bis(2-(dimethylamino)-2-phenylethanone),TFA salt (0.012 g, 21%)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.59-7.91 (20H, m) 5.62 (2H, dd, J=6.56,2.59 Hz) 4.99 (2H, d, J=8.85 Hz) 4.82/4.35 (2H, s) 4.22 (2H, s) 3.42(2H, s) 3.25 (2H, s) 2.35-2.61 (12H, m)

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate mobile phase t_(R)=3.128min.

Nominal/LRMS—Calcd. for C₄₄H₄₆N₈O₂S₂ 783.03. found 783.28 (M+H)⁺

Accurate/HRMS—Calcd. for C₄₄H₄₇N₈O₂S₂ 783.3263; 783.3246 (M+H)⁺

Examples 149 and 150 were prepared in similar fashion as described forthe preparation of example 148.

Example Compound Name Structure Data Example 149 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(4R)- 1,3-thiazolidine-4,3-diyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl))biscarbamate

t_(R) = 3.36 min (LCMS-Luna C- 18 3.0 × 50 mm, 0 to 100% B over 7.0minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammoniumacetate) LRMS: Anal. Calcd. for C₄₄H₄₂N₈O₆S₂ 842.99 found: 843.25 (M +H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₃N₈O₆S₂ 843.2747 found: 843.2724 (M +H)⁺ Example 150 (4R,4′R)-4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl))bis(3- ((2R)-tetrahydro-2- furanylcarbonyl)-1,3- thazolidine)

t_(R) = 4.32 min (HPLC-X-Terra C- 18 4.6 × 50 mm, 0 to 100% B over 10.0minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1%TFA, B = 90% methanol 10% water 0.1% TFA) LRMS: Anal. Calcd. forC₃₄H₃₆N₆O₄S₂ 656.83 found: 657.32 (M + H)⁺

Example 151(1R,1′R)-2,2′-(4,4′-biphenyldiylbis((1-methyl-1H-imidazole-4,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

Example 151 Step a

To a stirred solution of 1d, (2S,2′S)-tert-butyl2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate(100 mg, 0.16 mmole) and iodomethane (40 μL, 0.16 mmole) in CH₂Cl₂ (2mL) was added sodium hydride (40%) (21.2 mg, 0.352 mmole). After fivehours at ambient temperature, it was concentrated under reducedpressure. The crude reaction product 151a, (2S,2′S)-tert-butyl2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1-methyl-1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate(˜90 mg) was moved onto next step without further purification (purity˜85%) LCMS: Anal. Calcd. for: C₃₈H₄₈N₆O₄ 652.83. Found: 653.51 (M+H)⁺.It should be recognized that multiple methylation isomers are possiblein this reaction and no attempt to assign these was made.

Example 151 Step b

151a, (2S,2′S)-tert-butyl2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1-methyl-1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate(100 mg, 0.153 mmole) treated with 4 M HCl/dioxane (20 mL). After threehours at ambient temperature, it was concentrated under reducedpressure. The crude reaction product,4,4′-bis(1-methyl-2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl(˜110mg, HCl salt) was moved onto the next step without further purification(purity 85%) LCMS: Anal. Calcd. for: C₂₈H₃₂N₆ 452.59. Found: 453.38(M+H)⁺. Multiple imidazole isomers were present and carried forward.

Example 151

HATU (58.9 mg, 0.150 mmol) was added to a mixture of 151b,4,4′-bis(1-methyl-2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl(45.0 mg, 0.075 mmol), (i-Pr)₂EtN (78 μL, 0.451 mmol) and Cap-1,(R)-2-(dimethylamino)-2-phenylacetic acid (0.026 mg 0.150 mmol) in DMF(1.0 mL). The resultant mixture was stirred at ambient temperature untilthe coupling was complete as determined by LC/MS analysis. Purificationwas accomplished by reverse-phase preparative HPLC (Waters-Sunfire30×100 mm S5, detection at 220 nm, flow rate 30 mL/min, 0 to 90% B over14 min; A=90% water, 10% ACN, 0.1% TFA, B=10% water, 90% ACN, 0.1% TFA)to provide two isomer of 151,(2R,2′R)-1,1′-((2S,2′S)-2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1-methyl-1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-(dimethylamino)-2-phenylethanone),TFA salts.

Isomer 1:(1R,1′R)-2,2′-(4,4′-biphenyldiylbis((1-methyl-1H-imidazole-4,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(8 mg, 8.6%) as a colorless wax.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.84-2.25 (m, 8H) 2.32-2.90 (m, 12H)3.67-3.92 (m, 8H) 4.07 (s, 2H) 5.23 (s, 2H) 5.51 (s, 2H) 7.51-7.91 (m,20H)

HPLC Xterra 4.6×50 mm, 0 to 100% B over 10 minutes, one minutes holdtime, A=90% water, 10% methanol, 0.2% phosphoric acid, B=10% water, 90%methanol, 0.2% phosphoric acid, RT=2.74 min, 98%.

LCMS: Anal. Calcd. for: C₄₈H₅₄N₈O₂ 775.02. Found: 775.50 (M+H)⁺.

Isomer 2:(1R,1′R)-2,2′-(4,4′-biphenyldiylbis((1-methyl-1H-imidazole-4,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(10.2 mg, 11%) as a colorless wax.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.83-2.26 (m, 8H) 2.30-2.92 (m, 12H)3.68-3.94 (m, 8H) 4.06 (s, 2H) 5.25 (d, J=2.14 Hz, 2H) 5.50 (s, 2H)7.52-7.91 (m, 20H).

HPLC Xterra 4.6×50 mm, 0 to 100% B over 10 minutes, one minutes holdtime, A=90% water, 10% methanol, 0.2% phosphoric acid, B=10% water, 90%methanol, 0.2% phosphoric acid, RT=2.75 min, 90%.

LCMS: Anal. Calcd. for: C₄₈H₅₄N₈O₂ 775.02. Found: 775.52 (M+H)⁺.

Example 152

Example 152a-1 Step a 2-Chloro-5-(1-ethoxyvinyl)pyrimidine

To a solution of 5-bromo-2-chloropyrimidine (12.5 g, 64.62 mmol) in dryDMF (175 mL) under N₂ was added tributyl(1-ethoxyvinyl)tin (21.8 mL,64.62 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2.27 g,3.23 mmol). The mixture was heated at 100° C. for 3 h before beingallowed to stir at room temperature for 16 hr. The mixture was thendiluted with ether (200 mL) and treated with aqueous KF soln (55 g ofpotassium fluoride in 33 mL of water). The two phase mixture was stirredvigorously for 1 h at room temperature before being filtered throughdiatomaceous earth (Celite®). The filtrate was washed with sat'd NaHCO₃soln and brine prior to drying (Na₂SO₄). The original aqueous phase wasextracted with ether (2×) and the organic phase was treated as above.Repetition on 13.5 g of 5-bromo-2-chloropyrimidine and combinedpurification by Biotage™ flash chromatography on silica gel (gradientelution on a 65M column using 3% ethyl acetate in hexanes to 25% ethylacetate in hexanes with 3.0 L) afforded the title compound as a white,crystalline solid (18.2 g, 73%).

¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 2H), 5.08 (d, J=3.7 Hz, 1H), 4.56(d, J=3.4 Hz, 1H), 3.94 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=2.53 min, 98.8% homogeneity index.

LCMS: Anal. Calcd. for C₈H₁₀ClN₂O 185.05. found: 185.04 (M+H)⁺.

HRMS: Anal. Calcd. for C₈H₁₀ClN₂O 185.0482. found: 185.0490 (M+H)⁺.

The same method was used for the preparation of Examples 152a-2 &152a-3:

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152a-2

t_(R) = 2.24 min 96.4%, condition 1 LRMS: Anal. Calcd. for C₈H₁₀ClN₂O185.05; found: 185.06 (M + H)⁺. HRMS: Anal. Calcd for C₈H₁₀ClN₂O185.0482; found: 185.0476 (M + H)⁺. Example 152a-3

t_(R) = 2.82 min (52.7%, inseparable with 2,5- dibrompyrazine (t_(R) =1.99 min, 43.2%)); condition 1 LRMS: Anal. Calcd. for C₈H₁₀BrN₂O 229.00;found: 228.93 (M + H)⁺.

Example 152d-1 to 152d-6 Example 152b-1 Step b (S)-tert-Butyl2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateor(S)-2-[5-(2-Chloro-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

NBS (16.1 g, 90.7 mmol) was added in one portion to a stirred solutionof 2-chloro-5-(1-ethoxyvinyl)pyrimidine (152a-1, 18.2 g, 98.6 mmol) inTHF (267 mL) and H₂O (88 mL) at 0° C. under N₂. The mixture was stirredfor 1 h at 0° C. before it was diluted with more H₂O and extracted withethyl acetate (2×). The combined extracts were washed with sat'd NaHCO₃soln and brine prior to drying (Na₂SO₄), filtration, and solventevaporation. LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10%water, 90% methanol, 0.1% TFA, RT=1.52 min (unsymmetrical peak). LCMS:Anal. Calcd. for C₆H₁₄BrClN₂O 235.92. found: 236.85 (M+H)⁺.

Example 152c-1 Step c

Half of the crude residue (2-bromo-1-(2-chloropyrimidin-5-yl)ethanone,˜14.5 g) was dissolved into anhydrous acetonitrile (150 mL) and treateddirectly with N-Boc-L-proline (9.76 g, 45.35 mmol) anddiisopropylethylamine (7.9 mL, 45.35 mmol). After being stirred for 3 h,the solvent was removed in vacuo and the residue was partitioned intoethyl acetate and water. The organic phase was washed with 0.1Nhydrochloric acid, sat'd NaHCO₃ soln and brine prior to drying (Na₂SO₄),filtration, and concentration. LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.66 min.

The same method was used to prepare Examples 152c through 152c-6.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152c-2

t_(R) = 1.81 min (condition 2, ~95%) LRMS: Anal. Calcd. for C₁₅H₁₉BrN₄O₂386.05 found: 387.07 (M + H)⁺. Example 152c-3

t_(R) = 1.84 min (condition 2, 94%) LRMS: Anal. Calcd. for C₁₅H₁₉BrN₂O₅386.05; found: 387.07 (M + H)⁺. Example 152c-3a

t_(R) = 2.65 min; condition 1 LCMS: Anal. Calcd. for C₁₆H₂₀ClN₃O₅ 369.11found: 391.89 (M + Na)⁺. Example 152c-4

t_(R) = 1.94 min, (condition 2) LCMS: Anal. Calcd. for C₁₆H₂₁BrN₃O₅414.07 found: 414.11 (M + H)⁺. Example 152c-5

t_(R) = 2.22 min; condition 1 LCMS: Anal. Calcd. for C₁₄H₁₈ClN₃O₅ 343.09found: undetermined. Example 152c-6

t_(R) = 2.41 min, condition 1 LCMS: Anal. Calcd. for C₁₄H₁₈ ³⁷BrN₃O₅389.04 found: 412.03 (M + Na)⁺.

Example 152d-1 Step d

This residue ((S)-1-tert-butyl2-(2-(2-chloropyrimidin-5-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate)was taken up in xylenes (200 mL) and treated to NH₄OAc (17.5 g, 0.23mol). The mixture was heated at 140° C. for 2 hr in a thick-walled,screw-top flask before it was cooled to ambient temperature andsuction-filtered. The filtrate was then concentrated, partitioned intoethyl acetate and sat'd NaHCO₃ soln and washed with brine prior todrying (Na₂SO₄), filtration, and concentration The original precipitatewas partitioned into aqueous NaHCO₃ soln and ethyl acetate and sonicatedfor 2 min before being suction-filtered. The filtrate was washed withbrine, dried over (Na₂SO₄), filtered, and concentrated to dryness.Purification of the combined residues by Biotage™ flash chromatographyon silica gel (65M column, preequilibration with 2% B for 900 mLfollowed by gradient elution with 2% B to 2% B for 450 ml followed by 2%B to 40% B for 300 mL where B=methanol and A=dichloromethane) affordedthe title compound (7.0 g, 44% yield, 2 steps, pure fraction) as anyellowish orange foam. The mixed fractions were subjected to a secondBiotage™ chromatography on silica gel (40M column, preequilibration with1% B for 600 mL followed by gradient elution with 1% B to 1% B for 150ml followed by 1% B to 10% B for 1500 mL where B=MeOH and A=CH₂Cl₂)afforded additional title compound (2.8 g, 18%) as a brownish-orangefoam. ¹H NMR (500 MHz, DMSO-d₆) δ 12.24-12.16 (m, 1H), 9.05 (s, 2H),7.84-7.73 (m, 1H), 4.90-4.73 (m, 1H), 3.59-3.46 (m, 1H), 3.41-3.31 (m,1H), 2.32-2.12 (m, 1H), 2.03-1.77 (m, 3H), 1.39 and 1.15 (2s, 9H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=1.92 min, 94.7% homogeneity index.

LRMS: Anal. Calcd. for C₁₆H₂₁ClN₅O₂ 350.14. found: 350.23 (M+H)⁺.

HRMS: Anal. Calcd. for C₁₆H₂₁ClN₅O₂ 350.1384. found: 350.1398 (M+H)⁺.

The same method was used to prepare Examples 152d-2 through 152d-6.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152d-2

t_(R) = 1.92 min (86.5%); condition 1 LRMS: Anal. Calcd. forC₁₆H₂₁ClN₅O₂ 350.14; found: 350.23 (M + H)⁺. HRMS: Anal. Calcd. forC₁₆H₂₁ClN₅O₂ 350.1384; found: 350.1393 (M + H)⁺. Example 152d-3

t_(R) = 1.90 min (>95%); condition 1 LRMS: Anal. Calcd. for C₁₆H₂₁BrN₅O₂394.09; found: 393.82 (M + H)⁺. HRMS: Anal. Calcd. for C₁₆H₂₁BrN₅O₂394.0879; found: 394.0884 (M + H)⁺. Example 152d-4

t_(R) = 1.45 min (condition 2, 100%) LRMS: Anal. Calcd. for C₁₅H₁₉BrN₄O₂366.07 found: 367.07 (M + H)⁺. Example 152d-5

t_(R) = 1.88 min (>95%); condition 1 LRMS: Anal. Calcd. for C₁₄H₁₈BrN₅O₂367.06; found: 368.10 (M + H)⁺. Example 152d-6

t_(R) = 1.66 min (85%); condition 1 LRMS: Anal. Calcd. for C₁₄H₁₈ClN₅O₂323.11; found: 324.15 (M + H)⁺.

Example 152e-1 Step e Example 152e-1 (S)-tert-Butyl2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.72 mmol) wasadded in one portion to a stirred solution of (S)-tert-butyl2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(152d-1, 2.0 g, 5.72 mmol) in dry DMF (45 mL) at ambient temperatureunder N₂. The mixture was stirred for 5 min. before SEM chloride (1.01mL, 5.72 mmol) was added in approx. 0.1 mL increments. The mixture wasstirred for 3 h before being quenched with sat'd NH₄Cl soln and dilutedwith ethyl acetate. The organic phase was washed with sat'd NaHCO₃ solnand brine, dried over (Na₂SO₄), filtered, and concentrated. The originalaqueous phase was extracted twice more and the combined residue waspurified by Biotage™ flash chromatography (40M column, 50 mL/min,preequilibration with 5% B for 750 mL, followed by step gradient elutionwith 5% B to 5% B for 150 mL, 5% B to 75% B for 1500 mL, then 75% B to100% B for 750 mL where solvent B is ethyl acetate and solvent A ishexanes). Concentration of the eluant furnished the title compound as apale yellow foam (2.35 g, 85%).

¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.98-7.95 (m, 1H), 5.70-5.31(3m, 2H), 5.02-4.91 (m, 1H), 3.59-3.49 (m, 3H), 3.45-3.35 (m, 1H),2.30-2.08 (m, 2H), 1.99-1.83 (m, 2H), 1.36 and 1.12 (2s, 9H), 0.93-0.82(m, 2H), −0.02 (s, 9H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 2minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=2.38 min, 95% homogeneity index.

LRMS: Anal. Calcd. for C₂₂H₃₅ClN₅O₃Si 480.22. found: 480.23 (M+H)⁺.

HRMS: Anal. Calcd. for C₂₂H₃₅ClN₅O₃Si 480.2198. found: 480.2194 (M+H)⁺.

The same method was used to prepare 152e-2 through 152e-4

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152e-2

t_(R) = 2.34 min (85.7%); condition 1 LCMS: Anal. Calcd. forC₂₂H₃₅ClN₅O₃Si 480.22; found: 480.22 (M + H)⁺. HRMS: Anal. Calcd. forC₂₂H₃₅ClN₅O₃Si 480.2198 found: 480.2198 (M + H)⁺. Example 152e-3

t_(R) = 3.18 min (>95%); condition 1 LCMS: Anal. Calcd. for C₂₂H₃₅³⁷BrN₅O₃Si 526.17; found: 525.99 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₃₅³⁷BrN₅O₃Si 526.1692; found: 526.1674 (M + H)⁺. Example 152e-4

t_(R) = 2.14 min (condition 2, 96%) LRMS: Anal. Calcd. ForC₂₁H₃₃BrN₄O₃Si 496.15 found: 497.13 (M + H)⁺.

Examples 152f-1 to 152f-2 Example 152f-1(S)-1-(2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(pyridin-3-yl)ethanone

Cold (0° C.) 4 NHCl in dioxanes (5 mL) was added via syringe to(S)-tert-butyl2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(152d-1, 0.50 g, 1.43 mmol) in a 100 mL pear-shaped flask followed byMeOH (1.0 mL). The suspension was stirred at room temperature for 4 hbefore it was concentrated down to dryness and placed under high vacuumfor 1 h. There was isolated intermediate(S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidinetrihydrochloride as a pale yellow solid (with an orange tint) which wasused without further purification.

HATU (0.60 g, 1.57 mmol) was added in one portion to a stirred solutionof intermediate(S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidinetrihydrochloride (0.46 g, 1.43 mmol, theoretical amount),2-(pyridin-3-yl)acetic acid (0.25 g, 1.43 mmol) and DIEA (1.0 mL, 5.72mmol) in anhydrous DMF (10 mL) at ambient temperature. The mixture wasstirred at room temperature for 2 h before the DMF was removed in vacuo.The residue was taken up in CH₂Cl₂ and subjected to Biotage™ flashchromatography on silica gel (40M column, preequilibration with 0% B for600 mL followed by step gradient elution with 0% B to 0% B for 150 mLfollowed by 0% B to 15% B for 1500 mL followed by 15% B to 25% B for 999mL where B=MeOH and A=CH₂Cl₂). There was isolated the title compound(0.131 g, 25%, 2 steps) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.10-9.08 (2s, 2H), 8.72-8.55 (series of m,2H), 8.21-8.20 and 8.11-8.10 (2m, 1H), 8.00 and 7.93 (2s, 1H), 7.84-7.77(series of m, 1H), 5.43-5.41 and 5.17-5.15 (2m, 1H), 4.02-3.94 (3m, 2H),3.90-3.58 (3m, 2H), 2.37-2.26 (m, 1H), 2.16-1.85 (2m, 3H).

LCRMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=0.92 min, 95.1% homogeneity index.

LRMS: Anal. Calcd. for C₁₈H₁₈ClN₆O 369.12. found: 369.11 (M+H)⁺.

HRMS: Anal. Calcd. for C₁₈H₁₈ClN₆O 369.1231. found: 369.1246 (M+H)⁺.

Example 152f-2 LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injectionvolume.

Example 152f-2

t_(R) = 1.56 min (>95%) LRMS: Anal. Calcd. for C₂₀H₂₀BrN₄O 413.08;found: 412.99 (M + H)⁺.

Examples 152g-1 to 152g-16 Example 152g-1 from 1c and 152e-1(S)-2-[5-(2-{4-[2-((S)-1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

Pd (Ph₃)₄ (0.12 g, 0.103 mmol) was added in one portion to a stirredsuspension of (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1c, 1.00 g, 2.27 mmol), (S)-tert-butyl2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(152c-1, 0.99 g, 2.06 mmol) and NaHCO₃ (0.87 g, 10.3 mmol) in a solutionof DME (20 mL) and H₂O (6 mL) at room temperature under N₂. The vesselwas sealed and the mixture was placed into a preheated (80° C.) oil bathand stirred at 80° C. for 16 h before additional catalyst (0.12 g) wasadded. After heating the mixture for an additional 12 h at 80° C., themixture was cooled to ambient temperature, diluted with ethyl acetateand washed with sat'd NaHCO₃ soln and brine prior to drying overanhydrous sodium sulfate and solvent concentration. Purification of theresidue by Biotage™ flash chromatography on silica gel using a 40Mcolumn (preequilibrated with 40% B followed by step gradient elutionwith 40% B to 40% B for 150 mL, 40% B to 100% B for 1500 mL, 100% B to100% B for 1000 mL where B=ethyl acetate and A=hexanes) furnished thetitle compound as a yellow foam (1.533 g, 98%). A small amount of theyellow foam was further purified for characterization purposes by pHPLC(Phenomenex GEMINI, 30×100 mm, S10, 10 to 100% B over 13 minutes, 3minute hold time, 40 mL/min, A=95% water, 5% acetonitrile, 10 mM NH₄OAc,B=10% water, 90% acetonitrile, 10 mM NH₄OAc) to yield 95% pure titlecompound as a white solid.

¹HNMR (500 MHz, DMSO-d₆) δ 12.30-11.88 (3m, 1H), 9.17-9.16 (m, 2H),8.43-8.31 (m, 2H), 7.99-7.35 (series of m, 4H), 5.72-5.30 (3m, 2H),5.03-4.76 (2m, 2H), 3.64-3.50 (m, 4H), 3.48-3.31 (m, 2H), 2.36-2.07 (m,2H), 2.05-1.80 (m, 4H), 1.46-1.08 (2m, 18H), 0.95-0.84 (m, 2H), −0.01(s, 9H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=2.91 min, 95% homogeneity index.

LRMS: Anal. Calcd. for C₄₀H₅₇N₈O₅Si 757.42. found: 757.42 (M+H)⁺.

HRMS: Anal. Calcd. for C₄₀H₅₇N₈O₅Si 757.4221. found: 757.4191 (M+H)⁺.

The same procedure was used to prepare Examples 152g-2 through 152g-17:

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152g-2

t_(R) = 2.81 min (79%); Condition 1 LRMS: Anal. Calcd. for C₄₀H₅₇N₈O₅Si757.42; found: 758.05 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₅₇N₈O₅Si757.4221; found: 757.4196 (M + H)⁺. Example 152g-3

t_(R) = 2.89 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₀H₅₇N₈O₅Si757.42; found: 757.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₅₇N₈O₅Si757.4221; found: 757.4191 (M + H)⁺. Example 152g-4

t_(R) = 2.87 min (97%); Condition 1 LRMS: Anal. Calcd. forC₃₈H₅₅N₈O₅S_(i) 731.41; found: 731.26 (M + H)⁺. HRMS: Anal. Calcd. forC₃₈H₅₅N₈O₅S_(i) 731.4065; found: 731.4070 (M + H)⁺. Example 152g-5

t_(R) = 2.94 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₈H₅₅N₈O₅Si731.41; found: 731.26 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₅₅N₈O₅Si731.4065; found: 731.4046 (M + H)⁺. Example 152g-6

t_(R) = 1.99 min (condition 2, 96%) LRMS: Anal. Calcd. for C₃₇H₅₃N₇O₂Si703.39; found: 704.34 (M + H)⁺. Example 152g-7

t_(R) = 1.99 min (condition 2, 96%) LRMS: Anal. Calcd. for C₃₉H₅₅N₇O₅Si729.40; found: 730.42 (M + H)⁺. Example 152g-8

t_(R) = 2.15 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₇H₄₁N₈O₄661.33; found: 661.39 (M + H)⁺. HRMS: Anal. Calcd. for C₃₇H₄₁N₈O₄661.3251; found: 661.3268 (M + H)⁺. Example 152g-9

t_(R) = 1.71 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₆H₄₀N₉O₃646.76; found: 646.47 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₀N₉O₃ notdone found: not done (M + H)⁺. Example 152g- 10

t_(R) = 1.71 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₆H₄₀N₉O₃646.33; found: 646.37 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₀N₉O₃646.3254; found: 646.3240 (M + H)⁺. Example 152g- 11

t_(R) = 2.12 min (>93.9%); Condition 1 LRMS: Anal. Calcd. for C₃₃H₄₂N₇O₄600.33; found: 600.11 (M + H)⁺. HRMS: Anal. Calcd. for C₃₃H₄₂N₇O₄600.3298; found: 600.3312 (M + H)⁺. Example 152g- 12

t_(R) = 2.13 min (97.3%); Condition 1 LRMS: Anal. Calcd. for C₃₂H₄₁N₈O₄601.33; found: 601.36 (M + H)⁺. HRMS: Anal. Calcd. for C₃₂H₄₁N₈O₄601.3251; found: 601.3253 (M + H)⁺. Example 152g- 13

t_(R) = 2.11 min (98.5%); Condition 1 LRMS: Anal. Calcd. for C₃₂H₄₁N₈O₄601.33; found: 601.36 (M + H)⁺. HRMS: Anal. Calcd. for C₃₂H₄₁N₈O₄601.3251; found: 661.3253 (M + H)⁺. Example 152g- 14

t_(R) = 2.18 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₃H₄₃N₈O₄615.38; found: 615.36 (M + H)⁺. HRMS: Anal. Calcd. for C₃₃H₄₃N₈O₄615.3407; found: 615.3433 (M + H)⁺. Example 152g- 15

t_(R) = 2.20 min (97.7%); Condition 1 LRMS: Anal. Calcd. for C₃₅H₃₉N₈O₄635.31; found: 635.36 (M + H)⁺. HRMS: Anal. Calcd. for C₃₅H₃₉N₈O₄635.3094; found: 635.3119 (M + H)⁺. Example 152g- 16

t_(R) = 2.26 min (>95%); Condition 1 LRMS: Anal. Calcd. C₃₆H₄₁N₈O₄649.33; found: 649.39 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₁N₈O₄649.3251; found: 649.3276 (M + H)⁺. Example 152g- 17

t_(R) = 2.98 min (98.5%); Condition 1 LRMS: Anal. Calcd. forC₃₈H₅₄N₈O₅Si 730.39; found: 731.40 (M + H)⁺. HRMS: Anal. Calcd. forC₃₈H₅₄N₈O₅Si 731.4065; found: 731.4045 (M + H)⁺.

Example 152h-1-152h-7 Example 152h-1 from 152g-15-((S)-2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-2-[4-((S)-2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-pyrimidine

TFA (8 mL) was added in one portion to a stirred solution of(S)-2-[5-(2-{4-[2-((S)-1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (1.50 g, 1.98 mmol) in dry CH₂Cl₂ (30 mL) at roomtemperature. The flask was sealed and the mixture was stirred at roomtemperature for 16 h before the solvent(s) were removed in vacuo. Theresidue was taken up in methanol, filtered through a PVDF syringe filter(13 mm×0.45 μm), distributed to 8 pHPLC vials and chromatographed byHPLC (gradient elution from 10% B to 100% B over 13 min on a PhenomenexC18 column, 30×100 mm, 10 μm, where A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA). After concentration of theselected test tubes by speed vacuum evaporation, the product wasdissolved in methanol and neutralized by passing the solution through anUCT CHQAX 110M75 anion exchange cartridge. There was isolated the titlecompound as a yellow mustard-colored solid (306.7 mg, 36% yield) uponconcentration of the eluant.

¹H NMR (500 MHz, DMSO-d₆) μ 12.50-11.80 (br m, 2H), 9.18 (s, 2H), 8.36(d, J=8.5 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.77 (s, 1H), 7.61 (s, 1H),4.34-4.24 (m, 2H), 3.09-2.89 (m, 4H), 2.18-2.07 (m, 2H), 2.02-1.89 (m,2H), 1.88-1.72 (m, 4H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=1.33 min, >95% homogeneity index.

LRMS: Anal. Calcd. for C₂₄H₂₇N₈ 427.24. found: 427.01 (M+H)⁺.

HRMS: Anal. Calcd. for C₂₄H₂₇N₈ 427.2359. found: 427.2363 (M+H)⁺.

The same conditions were used to prepare Examples 152h-2 through152h-14.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152h-2

t_(R) = 1.36 min (98%); Condition 1 LRMS: Anal. Calcd. for C₂₄H₂₇N₈427.24; found: 427.48 (M + H)⁺. HRMS: Anal. Calcd. for C₂₄H₂₇N₈427.2359; found: 427.2339 (M + H)⁺. Example 152h-3

t_(R) = 1.17 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₅N₈401.22; found: 401.16 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₅N₈401.2202; found: 401.2193 (M + H)⁺. Example 152h-4

t_(R) = 1.28 min (89.3%); Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₅N₈401.22; found: 401.16 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₅N₈401.2202; found: 401.2201 (M + H)⁺. Example 152h-5

t_(R) = 0.93 min; Condition 2 LRMS: Anal. Calcd. for C₂₃H₂₅N₇ 399;found: 400 (M + H)⁺. Example 152h-6

t_(R) = 0.81 min; Condition 2 LRMS: Anal. Calcd. for C₂₁H₂₃N₇ 373;found: 374 (M + H)⁺. Example 152h-7

t_(R) = 1.14 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₂₃H₂₆N₇400.23; found: 400.14 (M + H)⁺. HRMS: Anal. Calcd. for C₂₃H₂₆N₇400.2250; found: 400.2234 (M + H)⁺. Example 152h-8

t_(R) = 1.29 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₅N₈401.22; found: 401.21 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₅N₈401.2202; found: 401.2204 (M + H)⁺. Example 152h-9

t_(R) = 1.29 min (97.6%); Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₅N₈401.22; found: 401.21 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₅N₈401.2202; found: 401.2220 (M + H)⁺. Example 152h-10

t_(R) = 1.26 min (86.4%); Condition 1 LRMS: Anal. Calcd. for C₂₄H₂₇N₈427.24; found: 427.48 (M + H)⁺. HRMS: Anal. Calcd. for C₂₄H₂₇N₈427.2359; found: 427.2339 (M + H)⁺. Example 152h-11

t_(R) = 1.26 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₁H₃₂N₉O546.27; found: 546.28 (M + H)⁺. HRMS: Anal. Calcd. for C₃₁H₃₂N₉O546.2730 found: 546.2739 (M + H)⁺. Example 152h-12

t_(R) = 1.39 min (95%); Condition 1 LRMS: Anal. Calcd. for C₃₁H₃₂N₉O546.27; found: 546.32 (M + H)⁺. HRMS: Anal. Calcd. for C₃₁H₃₂N₉O546.2730; found: 546.2719 (M + H)⁺. Example 152h-13

t_(R) = 1.42 min; Condition 1 LRMS: Anal. Calcd. for C₂₃H₂₆N₈ 414.24;found: 415.27 (M + H)⁺. HRMS: Anal. Calcd. for C₂₃H₂₆N₈ 415.2359; found:415.2371 (M + H)⁺. Example 152h-14

t_(R) = 1.30 min; Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₄N₈ 400.21;found: 401.24 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₄N₈ 401.2202; found:401.2198 (M + H)⁺.

Example 152i-1 to 152i-3 Example 152i-1 from 152g-8(S)-2-(5-{2-[4-((S)-2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-pyrimidin-5-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of(S)-2-[5-(2-{4-[2-((S)-1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added toa stirred suspension of 10% palladium on carbon (60 mg) and K₂CO₃ (70mg) in a solution of MeOH (5 mL) and H₂O (0.1 mL) at room temperatureunder N₂. The flask was charged and evacuated three times with H₂ andstirred for 3 h at atmosphere pressure. Additional catalyst (20 mg) wasthen added and the reaction mixture was stirred further for 3 h beforeit was suction-filtered through diatomaceous earth (Celite®) andconcentrated. The residue was diluted with MeOH, filtered through a PVDFsyringe filter (13 mm×0.45 μm), distributed into 4 pHPLC vials andchromatographed (gradient elution from 20% B to 100% B over 10 min on aPhenomenex-Gemini C18 column (30×100 mm, 10 μm) where A=95% water, 5%acetonitrile, 10 mM NH₄OAc, B=10% water, 90% acetonitrile, 10 mMNH₄OAc). After concentration of the selected test tubes by speed vacuumevaporation, there was isolated the title compound as a yellow solid(142.5 mg, 56% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 12.35-12.09 (br m, 1H), 9.17 (s, 2H), 8.35(d, J=8.3 Hz, 2H), 7.87 (d, J=8.3 Hz, 2H), 7.80-7.72 (m, 1H), 7.56 (s,1H), 4.92-4.77 (m, 1H), 4.21-4.13 (m, 1H), 3.61-3.05 (2m, 4H), 3.02-2.80(2m, 2H), 2.37-1.67 (series of m, 6H), 1.41 and 1.17 (2s, 9H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=1.77 min, >95% homogeneity index.

LRMS: Anal. Calcd. for C₂₉H₃₅N₈O₂ 527.29. found: 527.34 (M+H)⁺.

HRMS: Anal. Calcd. for C₂₉H₃₅N₈O₂ 527.2883. found: 527.2874 (M+H)⁺.

The same procedure was used to prepare Examples 152i-2 through 152i-3.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example 152i-2

t_(R) = 1.70 min (95.7%); Condition 1 LRMS: Anal. Calcd. for C₂₇H₃₃N₈O₂501.27; found: 501.35 (M + H)⁺. HRMS: Anal. Calcd. for C₂₇H₃₃N₈O₂ 501.27found: 501.35 (M + H)⁺. Example 152i-3

t_(R) = 1.77 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₂₈H₃₅N₈O₂515.29; found: 515.37 (M + H)⁺. HRMS: Anal. Calcd. for C₂₈H₃₅N₈O₂515.2883 found: 515.2869 (M + H)⁺.

Examples 152j-1 to 152j-28

Examples 152j were isolated as TFA or AcOH salts prepared using theprocedure to convert Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Compound Name Structure Data Example 152j-1(1R)-2-((2S)-2-(5-(2- (4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1-phenylethanamine

t_(R) = 1.61 min; (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₄H₄₉N₁₀O₂749.40 found: 749.32 (M + H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₉N₁₀O₂749.4040 found: 749.4042 (M + H)⁺ Example 152j-2 methyl ((1R)-2-((2S)-2-(5-(2-(4-(2-((2S)-1- ((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1- phenylethyl)-carbamate

t_(R) = 1.99 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₄H₄₅N₁₀O₆809.35 found: 809.17 (M + H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₅N₁₀O₆809.3524 found: 809.3505 (M + H)⁺ Example 152j-3 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4-(5-(2-((2S)-1- (3-pyridinylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)- carbamate

t_(R) = 1.65 min (92.3%); Condition 1 LRMS: Anal. Calcd. for C₄₁H₄₁N₁₀O₂737.33 found: 737.49 (M + H)⁺ HRMS: Anal. Calcd. for C₄₁H₄₁N₁₀O₄737.3312 found: 737.3342 (M + H)⁺ Example 152j-4 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(2-(4-(2-((2S)-1- (3-pyridinylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)- ethyl)carbamate

t_(R) = 1.64 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₁H₄₁N₁₀O₄737.33 found: 737.75 (M + H)⁺ HRMS: Anal. Calcd. for C₄₁H₄₁N₁₀O₄737.3312 found: 737.3284 (M + H)⁺ Example 152j-5 5-(2-((2S)-1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2-(4- (2-((2S)-1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)phenyl)pyrimidine

t_(R) = 1.70 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₅₀H₅₇N₁₀O₂829.47 found: 829.39 (M + H)⁺ HRMS: Anal. Calcd. for C₅₀H₅₇N₁₀O₂829.4666 found: 829.4658 (M + H)⁺ Example 152j-6 (2R)-N-methyl-2-phenyl-N-((1S)-1-(4- (4-(5-((2S)-1- ((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl)- 1H-imidazol-2- yl)ethyl)-2-(1-piperidinyl)acetamide

t_(R) = 1.66 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₉H₅₇N₁₀O₂817.47 found: 817.44 (M + H)⁺ HRMS: Anal. Calcd. for C₄₉H₅₇N₁₀O₂817.4666 found: 817.4673 (M + H)⁺ Example 152j-7 (1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-2- pyrazinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

t_(R) = 1.60 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₁H₄₉N₁₀O₂749.40 found: 749.31 (M + H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₉N₁₀O₂749.4040 found: 749.4031 (M + H)⁺ Example 152j-8 methyl ((1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1- ((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-2-pyrazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 2.01 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₄H₄₅N₁₀O₆809.35 found: 809.24 (M + H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₅N₁₀O₆809.3523 found: 809.3493 (M + H)⁺ Example 152j-9 (1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-3- pyridazinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine

t_(R) = 1.76 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₄H₄₉N₁₀O₂749.40 found: not obsd (M + H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₉N₁₀O₂749.4040 found: 749.4056 (M + H)⁺ Example 152j-10 methyl ((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-3-pyridazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 2.17 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₄H₄₅N₁₀O₆809.35 found: 809.59 (M + H)⁺ HRMS: Anal. Calcd. for C₄₄H₄₅N₁₀O₆809.3524 found: 809.3499 (M + H)⁺ Example 152j-11 (2R)-2-(dimethylamino)-N- ((1S)-1-(5-(4-(5-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyridinyl)phenyl)- 1H-imidazol-2- yl)ethyl)-2- phenylacetamide

t_(R) = 1.56 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₃H₄₈N₉O₂722.39 found: 722.89 (M + H)⁺ HRMS: Anal. Calcd. for C₄₃H₄₈N₉O₂ 722.3931found: 722.3930 (M + H)⁺ Example 152j-12 methyl ((1R)-2-((2S)-2-(5-(6-(4-(2-((1S)- 1-(((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino- ethyl)-1H-imidazol-5- yl)phenyl)-3- pyridinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.95 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₃H₄₄N₉O₆782.34 found: 782.93 (M + H)⁺ HRMS: Anal. Calcd. for C₄₃H₄₄N₉O₆ 782.3415found: 782.3398 (M + H)⁺ Example 152j-13 (2R)-2- (dimethylamino)-N-((1S)-1-(5-(4-(6-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3-pyridazinyl)phenyl)- 1H-imidazol-2- yl)ethyl)-2- phenylacetamide

t_(R) = 1.55 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₇N₁₀O₂723.39 found: 723.88 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₇N₁₀O₂723.3883 found: 723.3903 (M + H)⁺ Example 152j-14 methyl ((1R)-2-((2S)-2-(5-(6-(4-(2-((1S)- 1-(((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino- ethyl)-1H-imidazol-5- yl)phenyl)-3- pyridazinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.95 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.34 found: 783.95 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.3367 found: 783.3337 (M + H)⁺ Example 152j-15 methyl ((1R)-2-((2S)-2-(5-(2-(4-(2-((1S)- 1-(((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino)- ethyl)-1H-imidazol-5- yl)phenyl)-5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 1.97 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.34 found: 783.97 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.3367 found: 783.3357 (M + H)⁺ Example 152j-16 (2R)-2-(dimethylamino)-N- ((1S)-1-(5-(2-(4-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-phenyl)-5- pyrimidinyl)-1H- imidazol-2- yl)ethyl)-2- phenylacetamide

t_(R) = 1.61 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₇N₁₀O₂723.39 found: 723.52 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₇N₁₀O₂723.3883 found: 723.3893 (M + H)⁺ Example 152j-17 methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((1S)-1- (((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino- ethyl)-1H-imidazol-5- yl)-2- pyrimidinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.99 min (95.6%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.34 found: 783.44 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.3367 found: 783.3328 (M + H)⁺ Example 152j-18 (2R)-2-(dimethylamino)-N- ((1S)-1-(5-(5-(4-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-phenyl)-2- pyrazinyl)-1H- imidazol-2- yl)ethyl)-2- phenylacetamide

t_(R) = 1.60 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₇N₁₀O₂723.39 found: 723.47 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₇N₁₀O₂723.3883 found: 723.3861 (M + H)⁺ Example 152j-19 methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((1S)-1- (((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino)- ethyl)-1H-imidazol-5- yl)-2- pyrazinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.97 min (94.7%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.34 found: 783.69 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.3367 found: 783.3345 (M + H)⁺ Example 152j-20 (2R)-2-(dimethylamino)-N- ((1S)-1-(5-(4-(5-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimindinyl)phenyl)- 1H-imidazol-2- yl)ethyl)-N-methyl-2-phenylacetamide

t_(R) = 1.54 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₃H₄₉N₁₀O₂737.40 found: 737.54 (M + H)⁺ HRMS: Anal. Calcd. for C₄₃H₄₉N₁₀O₂737.4040 found: 7374066 (M + H)⁺ Example 152j-21 methyl ((1R)-2-((2S)-2-(5-(2-(4-(2-((1S)-1- (((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)(methyl)- amino)ethyl)-1H- imidazol-5- yl)phenyl)-5-pyrimidinyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 2.00 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₃H₄₅N₁₀O₆797.35 found: 797.38 (M + H)⁺ HRMS: Anal. Calcd. for C₄₃H₄₅N₁₀O₆797.3524 found: 797.3528 (M + H)⁺ Example 152j-22 methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((1S)-1- (((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino)- ethyl)-1H-imidazol-5- yl)-2- pyridinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.46 min (condition 2, 98%) LRMS: Anal. Calcd. for C₄₃H₄₃N₉O₆781.33; found: 782.34 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₄₄N₉O₆782.3415 found: 782.3417 (M + H)⁺ Example 152j-23 methyl ((1R)-2-(((1S)-1-(5-(6-(4-(2- ((1S)-1-(((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)amino)- ethyl)-1H-imidazol-5- yl)phenyl)-3- pyridinyl)-1H-imidazol-2-yl)- ethyl)amino)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.44 min condition 2, 90%) LRMS: Anal. Calcd. for C₄₁H₄₁N₉O₆755.32; found: 756.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₂N₉O₆756.3258 found: 756.3239 (M + H)⁺. Example 152j-24 (2R)-2-(dimethylamino)- N-((1S)-1-(5-(6- (4-(2-((1S)-1-(((2R)- 2-(dimethyl-amino)-2- phenylacetyl)amino)- ethyl)-1H-imidazol-5- yl)phenyl)-3-pyridinyl)-1H- imidazol-2-yl)- ethyl)-2- phenylacetamide

t_(R) = 1.18 min (condition 2, 91%) LRMS: Anal. Calcd. for C₄₁H₄₅N₉O₂695.37; found: 696.37 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₆N₉O₂696.3774 found: 696.3806 (M + H)⁺. Example 152j-25

t_(R) = 2.08 min (95.8%); Condition 1 LRMS: Anal. Calcd. for C₃₈H₄₄N₉O₅706.35; found: 706.53 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₄N₉O₅706.3465; found: 706.3492 (M + H)⁺. Example 152j-26

t_(R) = 2.04 min (96.4%); Condition 1 LRMS: Anal. Calcd. for C₃₇H₄₂N₉O₅692.33; found: 692.49 (M + H)⁺. HRMS: Anal. Calcd. for C₃₇H₄₂N₉O₅692.3309; found: 692.3322 (M + H)⁺. Example 152j-27

t_(R) = 2.04 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₉H₄₄N₉O₅718.35; found: 718.49 (M + H)⁺. HRMS: Anal. Calcd. for C₃₉H₄₄N₉O₅718.3465; found: 718.3483 (M + H)⁺. Example 152j-28 methyl((1R)-2-((2S)- 2-(5-(5-(4-(2-((1S)-1- (((2R)-2- ((methoxycarbonyl)-amino)-2- phenylacetyl)amino)- ethyl)-1H-imidazol-5- yl)phenyl)-2-pyazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 2.00 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.34 found: 783.96 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₀O₆783.3367 found: 783.3375 (M + H)⁺

Examples 152k-1 to 152k- Example 152k-1 from 152j-27{(R)-2-Oxo-1-phenyl-2-[(S)-2-(5-{4-[5-((S)-2-pyrrolidin-2-yl-3H-imidazol-4-yl)-pyrimidin-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-ethyl}-carbamicacid methyl ester

Cold (0° C.) 4 NHCl in dioxanes (4 mL) was added via syringe to(S)-2-{5-[2-(4-{2-[(S)-1-((R)-2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-pyrimidin-5-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (104.6 mg, 0.146 mmol) in a 100 mL pear-shapedflask followed by MeOH (0.5 mL). The homogeneous mixture was stirred atroom temperature for 15 min before a precipitate was observed. Afterstirring further for 1.75 h, the suspension was diluted with ether andhexanes. Suction-filtration of a small portion of the suspension yieldedthe title compound as a yellow solid which was used for characterizationpurposes. The balance of the suspension was concentrated down to drynessand placed under high vacuum for 16 h. There was isolated the rest ofthe title compound also as a yellow solid (137.7 mg, 123%) which wasused without further purification.

¹H NMR (500 MHz, DMSO-d₆) δ 15.20 and 14.66 (2m, 1H), 10.29 (br s,0.7H), 9.38-9.36 (m, 2H), 8.55-8.00 (series of m, 4H), 7.42-7.28 (2m,3H), 5.53-4.00 (series of m, 7H), 3.99-3.13 (series of m, 4H), 3.57 and3.52 (2s, 3H), 2.50-1.84 (series of m, 8H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=1.79 min, >95% homogeneity index.

LRMS: Anal. Calcd. for C₃₄H₃₆N₉O₃ 618.29. found: 618.42 (M+H)⁺.

HRMS: Anal. Calcd. for C₃₄H₃₆N₉O₃ 618.2921. found: 618.2958 (M+H)⁺.

The same procedure was used to prepare Examples 152k-2 through 152k-3.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Compound Name Structure Data Example 152k-2

t_(R) = 1.74 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₂H₃₄N₉O₃592.28; found: 592.41 (M + H)⁺. HRMS: Anal. Calcd. for C₃₂H₃₄N₉O₃592.2785; found: 592.2775 (M + H)⁺. Example 152k-3

t_(R) = 1.79 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₃₃H₃₆N₉O₃606.29; found: 606.43 (M + H)⁺. HRMS: Anal. Calcd. for C₃₃H₃₆N₉O₃606.2941; found: 606.2925 (M + H)⁺.

Examples 152l-1 to 152l-

Examples 152l-1 through 152l-3 were isolated as TFA or AcOH saltsprepared using the same procedure to convert Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Compound Name Structure Data Example 1521-1 methyl ((1R)-2-(methyl((1S)-1-(4-(4-(5- (2-((2S)-1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl-1H- imidazol-2- yl)ethyl)amino)-2-oxo-1-phenylethyl)carbamate

t_(R) = 1.87 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₆H₅₁N₁₀O₄807.41 found: 807.57 (M + H)⁺ HRMS: Anal. Calcd. for C₄₆H₅₁N₁₀O₄807.4095 found: 807.4128 (M + H)⁺ Example 1521-2 methyl ((1R)-2-oxo-1-phenyl-2-(((1S)-1-(4-(4- (5-(2-((2S)-1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl)-1H- imidazol-2- yl)ethyl)amino)ethyl) carbamate

t_(R) = 1.83 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₅H₄₉N₁₀O₄793.39 found: 793.52 (M + H)⁺ HRMS: Anal. Calcd. for C₄₅H₄₉N₁₀O₄793.3938 found: 793.3934 (M + H)⁺ Example 1521-3 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4- (5-(2-((2S)-1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) carbamate

t_(R) = 1.87 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₇H₅₁N₁₀O₄819.41 found: 819.50 (M + H)⁺ HRMS: Anal. Calcd. for C₄₇H₅₁N₁₀O₄819.4095 found: 819.4127 (M + H)⁺

Example 153a-1 from 153a-4 Example 153a-1 prepared from 152e-1(S)-2-[5-{5′-[2-((S)-1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-[2,2′]bipyrimidinyl-5-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

To a stirred solution of (S)-tert-butyl2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.0 g, 2.08 mmol) and dichlorobis(benzonitrile) palladium (40 mg, 0.104mmol) in dry DMF (10 mL) at room temperature under argon was added neattetrakis(dimethylamino)ethylene (1.0 mL, 4.16 mmol). The mixture washeated to 60° C. for 15 h before it was diluted with ethyl acetate andsuction-filtered through diatomaceous earth (Celite®). The filtrate waswashed with sat'd NaHCO₃ soln and brine prior to drying over Na₂SO₄ andsolvent evaporation. Purification of the residue by Biotage™ flashchromatography on silica gel (step gradient elution with 15% B to 15% Bfor 150 mL, 15% B to 75% B for 1500 mL, 75% B to 100% B for 1000 mL,100% B to 100% B for 1000 mL where B=ethyl acetate and A=hexane followedby a second gradient elution with 10% B to 100% B for 700 mL whereB=methanol and A=ethyl acetate) furnished the title compound as acaramel-colored, viscous oil (487.8 mg, 26% yield).

¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (s, 4H), 8.09-8.06 (m, 2H), 5.73-5.66and 5.50-5.44 (2m, 2H), 5.06-4.93 (m, 2H), 3.60-3.39 (2m, 8H), 2.32-2.08(3m, 4H), 2.00-1.85 (m, 4H), 1.37 and 1.14 (2s, 18H), 0.95-0.84 (m, 4H),−0.01 (s, 18H).

LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=3.37 min, >95% homogeneity index.

LRMS: Anal. Calcd. for C₄₄H₆₉N₁₀O₆S_(i2) 889.49. found: 889.57 (M+H)⁺.

HRMS: Anal. Calcd. for C₄₄H₆₉N₁₀O₆S_(i2) 889.4940. found: 889.4920(M+H)⁺.

The same procedure was used to prepare Examples 153a-2 through 153a-4.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Compound Example Name Structure Data Example 153a-2

t_(R) = 3.37 min (89.6%); Condition 1 LRMS: Anal. Calcd. forC₄₄H₆₉N₁₀O₆Si₂ 889.49; found: 889.56 (M + H)⁺. HRMS: Anal. Calcd. forC₄₄H₆₉N₁₀O₆Si₂ 889.494; found: 889.4951 (M + H)⁺. Example 153a-3

t_(R) = 3.37 min (95%); Condition 1 LRMS: Anal. Calcd. forC₄₄H₆₉N₁₀O₆Si₂ 889.49; found: 889.51 (M + H)⁺. HRMS: Anal. Calcd. forC₄₄H₆₉N₁₀O₆Si₂ 889.4940; found: 889.4915 (M + H)⁺. Example 153a-4

t_(R) = 2.3 min (condition 2) LRMS: Anal. Calcd. for C₄₂H₆₆N₈Si₂ 834;found: 835 (M + H)⁺.

Example 153b-1-153b-3

The hydrolysis reactions was performed as above for Example 152h.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Compound Name Structure Data Example 153b-1

t_(R) = 1.18 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₅N₁₀429.23; found: 429.01 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₅N₁₀429.2264; found: 429.2259 (M + H)⁺. Example 153b-2

t_(R) = 1.26 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₁H₄₁N₁₀O₂737.33 found: 737.49 (M + H)⁺ HRMS: Anal. Calcd. for C₄₁H₄₁N₁₀O₄737.3312 found: 737.3342 (M + H)⁺ Example 153b-3

t_(R) = 1.40 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₂₂H₂₅N₁₀429.23; found: 429.20 (M + H)⁺. HRMS: Anal. Calcd. for C₂₂H₂₅N₁₀:429.2264; Found: 429.2254 (M + H)⁺ Example 153b-4

t_(R) = 0.85 min (condition 1) LCMS: Anal. Calcd. for C₂₀H₂₂N₈ 374;found 375 (M + H)⁺.

Examples 153c-1 to 153c-7

Examples 153c-1 through 153c-7 were isolated as TFA or AcOH salts usingthe procedure used to convert Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% Bover 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA,B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water,90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Example Compound Name Structure Data Example 153c-1 (1R,1′R)-2,2′-(3,3′-bipyridazine-6,6′- diylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl)) bis(N,N-dimethyl-2- oxo-1- phenylethanamine)

t_(R) = 1.55 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₇N₁₂O₂751.39 found: 751.64 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₇N₁₂O₂751.3945 found: 751.3936 (M + H)⁺ Example 153c-2 dimethyl (3,3′-bipyridazine-6,6′- diylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl))) biscarbamate

t_(R) = 1.95 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₂O₆811.34 found: 811.22 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₂O₆811.3429 found: 811.3406 (M + H)⁺ Example 153c-3 (1R,1′R)-2,2′-(2,2′-bipyrimidine-5,5′- diylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N, N-dimethyl-2-oxo-1- phenylethanamine)

t_(R) = 1.51 min (>90%*); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₇N₁₂O₂751.39 found: 751.21 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₇N₁₂O₂751.3945 found: 751.3921 (M + H)⁺ Example 153c-4 dimethyl (2,2′-bipyrimidine-5,5′- diylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl))) biscarbamate

t_(R) = 1.88 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₂O₆811.34 found: 811.10 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₂O₆811.3429 found: 811.3401 (M + H)⁺ Example 153c-5 (1R,1′R)-2,2′-(2,2′-bipyrazine-5,5′- diylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl)) bis(N,N-dimethyl- 2-oxo-1-phenyl- ethanamine)

t_(R) = 1.61 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₇N₁₂O₂751.39 found: 751.30 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₇N₁₂O₂751.3945 found: 751.3943 (M + H)⁺ Example 153c-6 dimethyl (2,2′-bipyrazine-5,5′- diylbis(1H-imidazole- 5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl))) biscarbamate

t_(R) = 2.00 min (>95%); Condition 1 LRMS: Anal. Calcd. for C₄₂H₄₃N₁₂O₆811.34 found: 811.23 (M + H)⁺ HRMS: Anal. Calcd. for C₄₂H₄₃N₁₂O₆811.3429 found: 811.3407 (M + H)⁺ Example 153c-7 dimethyl (2,2′-bipyridine-5,5′- diylbis(1H-imidazole- 5,2-diyl(1S)-1,1-ethanediylimino((1R)- 2-oxo-1-phenyl-2,1- ethanediyl))) biscarbamate

t_(R) = 1.42 min (condition 2, 94%) LRMS: Anal. Calcd. for C₄₀H₄₀N₁₀O₆756.31; found: 757.34 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₀N₁₀O₆757.3211 found: 757.3180 (M + H)⁺.Section LS LC Conditions:

Condition 1: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 3.0×5.0 mm S10;Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min witha 1 min hold time

Condition 2: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min witha 1 min hold time

Condition 3: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Phenomenex 10u C18 4.6×5.0 mm; Wavelength: 220 nM; Flow rate: 4mL/min; 0% B to 100% B over 4 min with a 1 min hold time

Condition 4: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Luna 4.6×50 mm S10; Wavelength: 220 nM; Flow rate: 4 mL/min; 0%B to 100% B over 3 min with a 1 min hold time

Condition 5: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 3 min witha 1 min hold time

Condition 6: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Phenomenex-Luna 3.0×50 mm S10; Wavelength: 220 nM; Flow rate: 4mL/min; 0% B to 100% B over 8 min with a 2 min hold time

Condition 7: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 3.0×5.0 mm S10;Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 3 min witha 1 min hold time

Condition 8: Solvent A: 10% methanol/90% water/0.2% H₃PO₄; Solvent B:90% methanol/10% water/0.2% H₃PO₄; Column: YMC ODS-A 4.6×50 mm S5;Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min witha 1 min hold time

Condition 9: Solvent A: 10% methanol/90% water/0.2% H₃PO₄; Solvent B:90% methanol/10% water/0.2% H₃PO₄; Column: YMC ODS-A 4.6×50 mm S5;Wavelength: 220 nM; Flow rate: 2.5 mL/min; 0% B to 50% B over 8 min witha 3 min hold time

Condition 10: Xbridge C18, 150×4.6 mm I.D. S-3.5 um; Mobile Phase A: 95%Water-5% Acetonitrile with 10 mM ammonium acetate (pH=5); Mobile phaseB: 95% Acetonitrile-5% Water with 10 mM ammonium acetate (pH=5);Isocratic 30% B for 20 min; Flow rate: 1 mL/min; UV detection: 220 nm

Condition 11: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 mL/min; 30% B to 100% B over 4 min witha 1 min hold time

Condition 12: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 mL/min; 20% B to 100% B over 4 min witha 1 min hold time

Condition 13: Solvent A: 10% methanol/90% water/0.2% H₃PO₄; Solvent B:90% methanol/10% water/0.2% H₃PO₄; Column: YMC ODS-A 4.6×50 mm S5;Wavelength: 220 nM; Flow rate: 2.5 mL/min; 0% B to 100% B over 8 minwith a 3 min hold time

Section LS Preparative HPLC Conditions:

Condition 1: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 30×100 mm S10;Wavelength: 220 nM; Flow rate: 30 mL/min; 0% B to 100% B over 10 minwith a 2 min hold time

Condition 2: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Xterra Prep MS C18 30×50 mm 5u;Wavelength: 220 nM; Flow rate: 30 mL/min; 0% B to 100% B over 8 min witha 3 min hold time

Condition 3: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Xterra Prep MS C18 30×50 mm 5u;Wavelength: 220 nM; Flow rate: 25 mL/min; 10% B to 100% B over 8 minwith a 2 min hold time

Condition 4: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Xterra 19×100 mm S5; Wavelength:220 nM; Flow rate: 20 mL/min; 30% B to 100% B over 5 min with a 3 minhold time

Condition 5: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90%methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 30×100 mm S10;Wavelength: 220 nM; Flow rate: 30 mL/min; 10% B to 100% B over 8 minwith a 2 min hold time

Condition 6: Solvent A: 10% Acetonitrile/90% water/0.1% TFA; Solvent B:90% Acetonitrile/10% water/0.1% TFA; Column: Phenomenex-Luna 21×100 mmS10; Wavelength: 220 nM; Flow rate: 25 mL/min; 0% B to 60% B over 10 minwith a 5 min hold time

Experimentals:

Compound LS2(1S,1′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(1-cyclohexyl-2-oxoethanol)

Step a: To 1d (1.4 g; 2.24 mmol) was added 30 mL 4N HCl in dioxane.After 3 h, 60 mL ether was added and the precipitate was filtered anddried under high vacuum providing 1.02 g (80%) intermediate LS1 as apale yellow powder. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): δ 10.41 (s,2H), 9.98 (s, 2H), 8.22 (s, 2H), 8.06 (d, J=8.54 Hz, 4H), 7.92 (d,J=8.55 Hz, 4H), 5.07 (s, 2H), 3.43-3.54 (m, 2H), 3.33-3.43 (m, 2H),2.43-2.59 (m, 4H), 2.16-2.28 (m, 2H), 1.94-2.09 (m, 2H). LC (Cond. 1):RT=1.28 min; MS: Anal. Calcd. for [M+H]⁺ C₂₆H₂₈N₆: 425.24. found 425.56.

Step b: To intermediate LS1 (200 mg; 0.35 mmol) in 2 mL DMF was addedDIPEA (0.30 mL; 1.75 mmol), (S)-2-cyclohexyl-2-hydroxyacetic acid (61mg; 0.39 mmol), followed by HATU (147 mg; 0.38 mmol). After stirring atambient temperature for 18 h, the reaction mixture was split into twoportions and purified via preparative HPLC (Cond'n 1). Fractionscontaining desired product were pooled and passed through an MCXcartridge (Oasis; 6 g; preconditioned with two column lengths ofmethanol). The cartridge was washed with two column lengths of methanoland product was eluted with ammonia/methanol. Concentration provided 65mg of LS2 (26%) as a colorless powder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.87-1.30 (m, 12H) 1.38-1.53 (m, J=24.72, 11.90 Hz, 4H) 1.54-1.75 (m,8H) 1.95-2.21 (m, 6H) 3.72-3.86 (m, 6H) 5.13 (t, J=6.56 Hz, 2H) 7.87 (d,J=7.93 Hz, 4H) 7.96 (d, J=6.41 Hz, 4H) 8.13 (s, 2H) (imidazole NH andhydroxyl protons unaccounted for). LC (Cond'n 2): RT=3.07 min; MS: Anal.Calcd. for [M+H]⁺ C₄₂H₅₂N₆O₄: 705.9. found 705.6.

The following analogs were prepared in similar fashion to thepreparation of LS2 from intermediate LS1 employing the appropriatecarboxylic acid:

Example Number Compound Name Structure Analytical Data LS3(2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl))bis (4-methyl-1-oxo-2- pentanol)

LC/MS: 2.02 min (Cond'n 1); Anal. Calcd. for [M + H]⁺ C₃₈H₄₈N₆O₄: 653.4;found 653.2. LS4 (2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis (3-methyl-1-oxo-2- butanol)

LC/MS: 1.99 min (Cond'n 3); Anal. Calcd. for [M + H]⁺ C₃₆H₄₄N₆O₄: 625.3;found 625.3. LS16 3-buten-1-yl((1S)- 1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- (((3-buten-1- yloxy)carbonyl) amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

¹H NMR (500 MHz, CH₃OD) δ ppm 0.81-1.10 (m, 12 H) 1.90- 2.15 (m, 4 H)2.15-2.51 (m, 8 H) 3.82-3.96 (m, 2 H) 3.97- 4.05 (m, 2 H) 4.05-4.19 (m,4 H) 4.25 (d, J = 7.02 Hz, 2 H) 4.62 (s, 2 H) 5.00- 5.17 (m, 4 H) 5.20(t, J = 5.65 Hz, 2 H) 5.79- 5.93 (m, 2 H) 7.20-7.47 (m, 2 H) 7.59-7.90(m, 8 H)

Example LS6(2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N-methyl-1-oxo-2-propanamine)

Step a: To intermediate LS1 (64 mg; 0.11 mmol) in 1 mL DMF was added(S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (48 mg; 0.24mmol), Hunig's base (0.12 mL; 0.67 mmol) and HATU (90 mg; 0.24 mmol).After 3 h, the reaction was purified via preparative HPLC (Cond'n 2).Fractions containing intermediate LS5 were pooled and concentratedproviding intermediate LS5 as a colorless powder (43 mg; 48%) afterdrying under high vacuum. LC (Cond'n 4): RT=2.12 min; MS: Anal. Calcd.for [M+H]⁺ C₄₄H₅₈N₈O₆: 795.4. found 795.5.

Step b: Intermediate LS5 was allowed to stir in 2 mL HCl/Dioxane (4N)for 18 h at which time 10 mL ether was added and the resultantprecipitate was filtered and dried under high vacuum providing LS6 (45mg; 155%) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.00-2.11 (m, 2H) 2.12-2.27 (m, 4H) 2.38-2.47 (m, 2H) 2.39-2.48 (m, 2H)2.58 (t, J=5.19 Hz, 2H) 3.78-3.85 (m, 2H) 3.91-4.02 (m, 2H) 4.21-4.32(m, 2H) 5.26 (t, J=7.17 Hz, 2H) 7.93 (d, J=7.32 Hz, 4H) 8.02 (d, J=7.94Hz, 4H) 8.12-8.21 (m, 2H) 8.69-8.81 (m, 2H) 9.09-9.17 (m, 2H); N-Meprotons obscured by DMSO peak with 2 other protons unaccounted for. LC(Cond'n 5): RT=1.71 min; MS: Anal. Calcd. for [M+H]⁺ C₃₄H₄₂N₈O₂: 595.3.found 595.6.

Example LS11(4S,4′S)-4,4′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(1,3-oxazinan-2-one)

Step a: To intermediate LS1 (65 mg; 0.11 mmol) in 1 mL DMF was addedHATU (91 mg; 0.24 mmol), (S)-2-oxo-1,3-oxazinane-4-carboxylic acid(intermediate LS10; mg; 0.24 mmol), followed by DIPEA (0.12 mL; 0.68mmol. After 3 h, the reaction mixture was twice purified via preparativeHPLC (Cond'n 3). Appropriate fractions were pooled and concentratedunder high vacuum providing 8 mg (10%) bis TFA LS11 as a colorless oil.¹H NMR (500 MHz, CH₃OD) δ ppm ¹H NMR (500 MHz, CH₃OD) δ ppm 1.99-2.43(m, 10H) 2.48-2.66 (m, 1.98 Hz, 2H) 3.82-3.95 (m, 4H) 4.17-4.40 (m, 4H)4.57 (t, J=5.80 Hz, 2H) 5.23-5.41 (m, 2H) 7.73-7.97 (m, 10H); imidazoleand carbamate NH protons are unaccounted for. LC (Cond'n 6): RT=2.28min; MS: Anal. Calcd. for [M+H]⁺ C₃₄H₄₂N₈O₂: 679.3. found 679.4.

Step b: Performed as in Baldwin et al, Tetrahedron 1988, 44, 637

Step c: Performed as in Sakaitani and Ohfune, J. Am. Chem. Soc. 1990,112, 1150 for the conversion of compound 1 to 5. Purification viaBiotage (40M cartridge; 1:1 ether/ethyl acetate) then preparative HPLC(Cond'n 4) provided 77 mg (8%) intermediate LS9 as a viscous oil. ¹H NMR(300 MHz, CDCl₃) δ ppm 2.02-2.21 (m, 1H) 2.23-2.41 (m, 1H) 4.11-4.38 (m,3H) 5.11-5.31 (m, 2H) 6.15 (s, 1H) 7.27-7.46 (m, 5H). LC (Cond'n 7):RT=1.24 min; MS: Anal. Calcd. for [M+H]⁺ C₃₄H₄₂N₈O₂: 236.1. found 236.4.

Step d: Intermediate LS9 was hydrogenated under 1 atm H₂ in 3 mLmethanol with 10 mg Pd/C (10%) for 18 h. The reaction mixture wasfiltered through a pad of diatomaceous earth (Celite®) and concentratedto provide intermediate LS110 (40 mg; 83%) as a colorless powder. ¹H NMR(500 MHz, CH₃OD) δ ppm 2.08-2.18 (m, 1H) 2.26-2.38 (m, 1H) 4.19 (t,J=5.95 Hz, 1H) 4.25-4.40 (m, 2H).

Example LS1-4 methyl((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

Step a: To 28 (1.5 g; 2.86 mmol) in 25 mL DMF was added sequentiallyCap-2 (697 mg; 2.86 mmol), HATU (1.2 g; 3.14 mmol), and Hunig's base(1.5 mL; 8.57 mmol). After 3 h, the solution was concentrated to 10 mLand partitioned between chloroform and water. The organic layer waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to an amber oil which was subjected to silica gelchromatography (Biotage; loaded on 40 samplet with dichloromethane;eluted on 40M cartridge with 0 to 12% dichloromethane/methanol over 1200mL). Fractions containing intermediate LS12 were pooled and concentratedto provide material which contained residual DMF. This material wasredissolved in dichloromethane and washed with water (3×50 mL) and thenbrine. The organic layer was dried over magnesium sulfate, filtered, andconcentrated to 761 mg powder which was repurified via silica gelchromatography (Biotage; loaded on 40 samplet with dichloromethane;eluted on 40M cartridge with 0 to 80% 4:1 chloroform:methanol/ethylacetate over 1500 mL) to provide intermediate LS12 (501 mg; 25%) as acolorless powder. LC (Cond'n 8): RT=1.24 min.

Step b: To intermediate LS12 (490 mg; 0.69 mmol) was added 6 mLHCl/Dioxane followed by 25 mL dichloromethane. After 24 h, 75 mL etherwas added, the reaction mixture was filtered and the precipitate wasdried under vacuum providing intermediate LS13.4HCl (434 mg; quant) as atan solid. ¹H NMR (300 MHz, CH₃OD) δ ppm 1.16-1.29 (m, 3H) 1.37 (t,J=6.95 Hz, 3H) 1.89-2.06 (m, 6.95 Hz, 1H) 2.12-2.51 (m, 5H) 2.52-2.85(m, 4H) 3.02-3.24 (m, 2H) 3.42-3.55 (m, 7.32 Hz, 1H) 3.58-3.71 (m, 2H)4.26-4.41 (m, 1H) 5.18-5.37 (m, 2H) 5.65 (s, 1H) 7.57-7.66 (m, 3H)7.67-7.75 (m, 1H) 7.86-8.04 (m, 10H) 8.14 (s, 1H). LC (Cond'n 8):RT=1.92 min.

Step c: To intermediate LS13.4HCl (75 mg; 0.099 mmol) in 0.7 mL DMF wasadded sequentially intermediate LS16 (26 mg; 0.118 mmol), HATU (45 mg;0.118 mmol), and Hunig's base (0.10 mL; 0.591 mmol). After 2 h, thereaction mixture was filtered through diatomaceous earth (Celite®), thepad washed with 0.3 mL methanol and the resultant filtrate was purifiedvia preparative HPLC (Cond'n 5) in two separate injections. Thefractions containing desired product were passed through an MCXcartridge (Oasis; 1 g; preconditioned with two column lengths ofmethanol). The cartridge was washed with two column lengths of methanoland product was eluted with ammonia/methanol. Concentration provided 36mg of LS14 as a colorless powder which was assayed to be of 82%diastereomeric purity (most likely epimeric at the stereogenic carbon inintermediate 16). Resubjected to preparative HPLC purification (2×)providing LS14 (13 mg; 16%) as a colorless solid. ¹H NMR (500 MHz,CH₃OD) δ ppm 0.99 (q, J=6.92 Hz, 6H) 1.25-1.72 (m, 5H) 1.80-2.42 (m,10H) 2.47-2.61 (m, 3H) 2.66-2.78 (m, 2H) 3.35-3.43 (m, 2H) 3.65-3.71 (m,3H) 3.89-4.01 (m, 4H) 4.01-4.10 (m, 1H) 4.32 (d, J=8.24 Hz, 1H)5.11-5.22 (m, 1H) 6.95-7.17 (m, 3H) 7.30-7.44 (m, 3H) 7.53 (d, J=7.02Hz, 1H) 7.62-7.89 (m, 8H). LC (Cond'n 9): RT=5.31 min.

Step d: Intermediate LS16 was prepared in analogous fashion to theprocedure describing the synthesis of Cap-51 substituting(S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (available fromAstatech) for L-Valine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.15-1.63 (m,5H) 1.75-2.03 (m, 1H) 3.54 (s, 3H) 3.76-3.98 (m, 4H) 7.45 (d, J=8.42 Hz,1H); one proton obscured by water peak.

Example LS20 methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-methylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

Step a & b: Intermediate LS18 was prepared in analogous fashion to theprocedure describing the synthesis of intermediate LS13 substitutingCap-51 for Cap-2.

Step c: To intermediate LS18 (100 mg; 0.14 mmol) in 1.4 mL DMF was addedsequentially N-Boc Sarcosine (30 mg; 0.16 mmol), Hunig's base (0.13 mL;0.72 mmol) and HATU (60 mg; 0.16 mmol). After 2 h the reaction mixturewas partitioned into dichloromethane, washed with NaHCO₃ (aq), brine,dried over magnesium sulfate, filtered and concentrated to crudeintermediate LS19 which was used directly in the next step. LC (Cond'n5): RT=2.42 min; MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₂N₈O₆: 753.4. found753.9.

Step d: Crude intermediate LS19 was dissolved in 0.5 mL methanol and 5mL 4N HCl/Dioxane. After stirring for 1 h, the reaction was concentratedand purified via preparative HPLC (Cond'n 6) and the fractionscontaining desired product were passed through an MCX cartridge (Oasis;1 g; preconditioned with two column lengths of methanol). The cartridgewas washed with two column lengths of methanol and product was elutedwith ammonia/methanol. Concentration provided LS20 (32 mg; 34%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.74-0.98 (m, 6H) 1.79-2.24 (m, 9H) 2.29-2.38(m, 2H) 3.19-3.51 (m, 8H) 3.50-3.56 (m, 3H) 3.59-3.71 (m, 1H) 3.81 (s,1H) 3.97-4.17 (m, 1H) 5.01-5.16 (m, 2H) 7.30 (d, J=7.93 Hz, 1H) 7.51 (s,1H) 7.59-7.74 (m, 4H) 7.79 (d, J=7.63 Hz, 4H) 11.78 (s, 1H). LC (Cond'n5): RT=2.00 min; MS: Anal. Calcd. for [M+H]⁺ C₃₆H₄₄N₈O₄: 653.4. found653.7.

The following analogs were prepared in similar fashion to thepreparation of LS20 from LS18 substituting the appropriate carboxylicacid for N-Boc Sarcosine:

Example Number Compound Name Structure Analytical Data LS21 methyl((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- ethylglycyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2- methylpropyl carbamate

LC/MS: 2.34 min (Cond'n 2); Anal. Calcd. for [M + H]⁺ C₃₇H₄₆N₈O₄: 667.4;found 667.7. LS22 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N-benzylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LC/MS: 2.34 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₄₂H₄₈N₈O₄: 729.4;found 729.8. LS23 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N-isobutylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LC/MS: 2.07 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₃₉H₅₀N₈O₄: 695.4;found 695.8. LS24 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N-sec-butylylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LC/MS: 2.03 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₃₉H₅₀N₈O₄: 695.4;found 695.9. LS25 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N-isopropylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LC/MS: 1.97 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₃₈H₄₈N₈O₄: 681.4;found 681.7.

Example LS26 methyl ((1S)-1-(((2S)-2-(5-(4(2-((2S)-1-(N,N-diisopropylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Step a: Compound LS26 was prepared in a similar fashion to thepreparation of intermediate LS19 employing 2-(diisopropylamino)aceticacid as the carboxylic acid coupling partner. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.74-1.04 (m, 18H) 1.74-2.21 (m, 13H) 2.86-3.09 (m, 3H) 3.54 (s,3H) 3.71-3.89 (m, 3H) 4.06 (t, J=8.55 Hz, 1H) 4.98-5.13 (m, 2H) 5.56 (d,J=8.55 Hz, 1H) 7.21-7.34 (m, 1H) 7.42-7.54 (m, 1H) 7.61-7.87 (m, 8H). LC(Cond'n 5): RT=1.98 min; MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₄N₈O₄: 723.4.found 723.4.

Example LS27 Diastereomer 1 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-(3-oxetanyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamateExample LS27 Diastereomer 2 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(3-oxetanyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Step a: Compound LS27 was prepared in a similar fashion to thepreparation of intermediate LS19 employing2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetic acid (intermediate LS29)as the carboxylic acid coupling partner. The two diastereomers of LS27were separated via preparative HPLC (Xbridge C18, 100×19 mm I.D. S-5 μm;Mobile Phase A: 95% Water-5% Acetonitrile with 10 mM ammonium acetate(pH=5); Mobile phase B: 95% Acetonitrile-5% Water with 10 mM ammoniumacetate (pH=5); Isocratic 30% B for 7 min; Flow rate: 25 mL/min; UVdetection: 220 nm; Sample amount: ˜5 mg/each injection, 300 μl samplesolution in methanol (˜17 mg/mL)). Diastereomer 1: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.80-0.96 (m, 6H) 1.91-2.06 (m, 6H) 2.09-2.21 (m, 3H)3.54 (s, 3H) 3.59 (s, 3H) 3.77-3.83 (m, 2H) 3.87 (t, J=7.63 Hz, 1H) 4.06(t, J=8.24 Hz, 1H) 4.31 (t, J=6.41 Hz, 1H) 4.43 (t, J=6.10 Hz, 1H) 4.49(t, J=7.17 Hz, 1H) 4.51-4.57 (m, 1H) 4.80 (t, J=8.55 Hz, 1H) 5.00-5.05(m, 1H) 5.06-5.11 (m, 1H) 7.30 (d, J=8.55 Hz, 1H) 7.50 (s, 1H) 7.58-7.89(m, 8H) 11.77 (s, 2H). LC (Cond'n 10): RT=7.14 min; MS: Anal. Calcd. for[M+H]⁺ C₄₀H₄₈N₈O₇: 753.4. found 753.9. Diastereomer 2: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.79-0.98 (m, 6H) 1.91-2.06 (m, 4H) 2.07-2.23 (m, 4H)3.51-3.69 (m, 8H) 3.74-3.90 (m, 2H) 4.06 (t, J=7.48 Hz, 1H) 4.20-4.33(m, 1H) 4.36-4.49 (m, 2H) 4.55 (s, 2H) 4.71 (s, 1H) 4.97-5.05 (m, 1H)5.08 (s, 1H) 5.53 (s, 1H) 7.30 (d, J=7.93 Hz, 1H) 7.51 (s, 1H) 7.58-7.91(m, 8H) 11.53 (s, 1H) 11.78 (s, 1H). LC (Cond'n 10): RT=8.79 min; MS:Anal. Calcd. for [M+H]⁺ C₄₀H₄₈N₈O₇: 753.4. found 753.9.

Step b: A solution of methyl2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (intermediateLS28; Source: Moldes et al, Il Farmaco, 2001, 56, 609 and Wuitschik etal, Ang. Chem. Int. Ed. Engl, 2006, 45, 7736; 200 mg, 0.721 mmol) inethyl acetate (7 mL) and CH₂Cl₂ (4.00 mL) was degassed by bubblingnitrogen for 10 min. Dimethyl dicarbonate (0.116 mL, 1.082 mmol) andPd/C (20 mg, 0.019 mmol) were then added, the reaction mixture wasfitted with a hydrogen balloon and allowed to stir at ambienttemperature overnight. The reaction mixture was filtered throughdiatomaceous earth (Celite®) and concentrated. The residue was purifiedvia Biotage (load with dichloromethane on 25 samplet; elute on 25Scolumn with dichloromethane for 3CV then 0 to 5%methanol/dichloromethane over 250 mL then hold at 5%methanol/dichloromethane for 250 mL; 9 mL fractions). Fractionscontaining the desired product were concentrated to provide 167 mgmethyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorlessoil which solidified on standing. ¹H NMR (500 MHz, CHLOROFORM-D) δ ppm3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H)4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (br s, 1H). MS: Anal. Calcd.for [M+H]⁺ C₈H₁₃NO₅: 204.1. found 204.0. To methyl2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) inTHF (2 mL) and Water (0.5 mL) was added lithium hydroxide monohydrate(10.33 mg, 0.246 mmol). The resultant solution was allowed to stirovernight at ambient temperature then concentrated to dryness to provideintermediate LS29 as a colorless powder. ¹H NMR (500 MHz, CH₃OD) δ ppm3.38-3.50 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.63 Hz, 1H) 4.57-4.79 (m,4H).

Example LS36 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Step a: To(S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylicacid (intermediate LS30; 1.5 g; 4.3 mmol) in 50 mL DMF was addedsequentially 2-amino-1-(4-bromophenyl)ethanone hydrochloride (1.2 g; 4.7mmol), HOAT (290 mg; 2.1 mmol), Hunig's base (0.7 mL; 4.3 mmol) and EDCI(1.2 g; 6.4 mmol). After 1 h, the reaction mixture was poured into 150mL water and allowed to stir for 15 min before filtering the resultantprecipitate which was dissolved in dichloromethane and dried overmagnesium sulfate. The dichloromethane mixture was filtered and appliedto a Biotage 40 samplet. Chromatography on a 40M column (25 to 60% ethylacetate/hexane over 1200 mL) provided (S)-(9H-fluoren-9-yl)methyl2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate(intermediate LS31; 2.4 g; quant) as a yellow foam. LC (Cond'n 11):RT=3.75 min; MS: Anal. Calcd. for [M+H]⁺ C₂₉H₂₇BrN₂O₄: 547.1. found547.0.

Step b: A mixture of ammonium acetate (844 mg; 10.97 mmol) and(S)-(9H-fluoren-9-yl)methyl2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate(intermediate LS31; 1.00 g; 1.83 mmol) was heated to 140° C. in 25 mLxylene for 2.5 h at which time the reaction mixture was concentrated andloaded with dichloromethane onto a Biotage 40 samplet. Purification viaBiotage (5 to 60% ethyl acetate/hexane over 100 mL with 400 mL holdtime) provided (S)-(9H-fluoren-9-yl)methyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate(intermediate LS32; 469 mg; 49%) as an amber liquid. LC (Cond'n 12):RT=3.09 min; MS: Anal. Calcd. for [M+H]⁺ C₂₉H₂₆BrN₃O₂: 528.1. found528.5.

Step c: To (S)-(9H-fluoren-9-yl)methyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate(intermediate LS32; 329 mg; 0.62 mmol) in 3 mL DMF was added 1.5 mLpiperidine. The reaction mixture was concentrated via a nitrogen streamovernight. The resultant residue was washed with hexane and passedthrough an MCX cartridge (Oasis; 6 g; preconditioned with two columnlengths of methanol). The cartridge was washed with two column lengthsof methanol and product was eluted with ammonia/methanol. Concentrationprovided 193 mg of(S)-5-(4-bromophenyl)-2-(2-methylpyrrolidin-2-yl)-1H-imidazole which wasdissolved in 6 mL dichloromethane and combined withdi-t-butyldicarbonate (413 mg; 1.89 mmol), DMAP (15 mg; 0.13 mmol) andTEA (0.17 mL; 1.30 mmol). After 48 h, the reaction mixture wasconcentrated and purified via chromatography on a Biotage systemproviding (S)-tert-butyl5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-imidazole-1-carboxylate(intermediate LS33; 150 mg; 48%) as an off white solid. LC (Cond'n 5):RT=3.75 min; MS: Anal. Calcd. for [M+H]⁺ C₂₄H₃₂BrN₃O₄: 506.2. found506.4

Step d: (S)-tert-butyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate(intermediate LS34) was prepared in a similar fashion to the preparationof 1d employing intermediate LS33 in place of 1b. ¹H NMR (300 MHz,DMSO-d₆; 100° C.) δ ppm 1.18-1.29 (m, 9H) 1.29-1.40 (m, 9H) 1.75-1.82(m, 3H) 1.81-2.39 (m, 8H) 3.35-3.75 (m, 4H) 4.81-4.92 (m, 1H) 7.36-7.45(m, 1H) 7.57-7.74 (m, 5H) 7.76-7.89 (m, 4H) 11.29-11.63 (m, 2H). LC(Cond'n 5): RT=2.49 min; MS: Anal. Calcd. for [M+H]⁺ C₃₇H₄₆N₆O₄: 639.4.found 639.9.

Step e:2-((S)-2-methylpyrrolidin-2-yl)-5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazole(intermediate LS35) was prepared in a similar fashion to the preparationof 1e employing intermediate LS34 in place of 1d. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.76-1.83 (m, 3H) 1.92-2.23 (m, 6H) 3.31-3.49 (m, 4H)4.88-4.97 (m, 1H) 7.76-7.88 (m, 5H) 7.90-8.04 (m, 5H) 9.72-9.82 (m, 1H)10.04-10.16 (m, 1H); imidazole and pyrrolidine NH protons unaccountedfor. LC (Cond'n 5): RT=1.79 min; MS: Anal. Calcd. for [M+H]⁺ C₂₇H₃₀N₆:439.2. found 439.5.

Step f: Compound LS36 was prepared in a similar fashion to thepreparation of example 1 employing intermediate LS35 in place of 1e andCap-51 in place of Cap-1. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.72-0.97 (m,12H) 1.77 (s, 3H) 1.86-2.08 (m, 8H) 2.09-2.19 (m, 2H) 2.25-2.39 (m, 2H)3.49-3.59 (m, 6H) 3.81 (d, J=6.71 Hz, 4H) 4.06 (q, J=7.83 Hz, 2H) 5.08(dd, J=7.02, 3.05 Hz, 1H) 7.12 (d, J=8.85 Hz, 1H) 7.27-7.34 (m, 1H)7.46-7.55 (m, 1H) 7.59-7.73 (m, 4H) 7.75-7.86 (m, 3H) 11.66 (s, 1H)11.77 (s, 1H). LC (Cond'n 5): RT=2.25 min; MS: Anal. Calcd. for [M+H]⁺C₄₁H₅₂N₈O₆: 753.4. found 754.0.

Example LS37 methyl((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methyl-1-pyrrolidinyl)carbonyl)propyl)carbamate

Compound LS37 was prepared in a similar fashion to the preparation ofLS36 from intermediate LS30 using Cap-86 in place of Cap-51. ¹H NMR (500MHz, DMSO-d₆) δ ppm 0.99-1.17 (m, 6H) 1.76 (s, 3H) 1.87-2.09 (m, 4H)2.10-2.23 (m, 2H) 2.34-2.38 (m, 2H) 2.56-2.60 (m, 1H) 2.63 (d, J=1.83Hz, 1H) 3.17 (s, 3H) 3.19 (s, 3H) 3.37-3.51 (m, 2H) 3.54 (s, 6H)3.75-3.96 (m, 4H) 4.13-4.36 (m, 2H) 5.07 (dd, J=7.48, 3.20 Hz, 1H) 7.20(d, J=8.54 Hz, 1H) 7.24-7.34 (m, 1H) 7.50 (dd, J=7.17, 1.98 Hz, 1H)7.59-7.73 (m, 4H) 7.76-7.86 (m, 3H) 11.65 (s, 1H) 11.77 (s, 1H). LC(Cond'n 13): RT=4.30 min; MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₂N₈O₈: 785.4.found 785.4.

Section F LC Conditions for Determining Retention Time

Condition 1

Column: Phenomenex-Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient Time=4 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 2

Column: Waters-Sunfire 4.6×50 mm S5

Start % B=0

Final % B=100

Gradient Time=2 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 3

Column: Phenomenex 10u 3.0×50 mm

Start % B=0

Final % B=100

Gradient Time=2 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 4

Column: Phenomenex-Luna 3.0×50 mm S10

Start % B=0

Final % B=100

Gradient Time=3 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 5

Column: Phenomenex-Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient Time=3 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 6

Column: Xbridge C18 4.6×50 mm S5

Start % B=0

Final % B=100

Gradient Time=3 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=H₂O:ACN 95%:5% 10 mm Ammonium Acetate

Solvent B=H₂O:ACN 5%:95% 10 mm Ammonium Acetate

Condition 7

Column: Phenomenex C18 10u 4.6×30 mm

Start % B=0

Final % B=100

Gradient Time=3 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 8

Column: Phenomenex LunaC18 10u 4.6×30 mm

Start % B=0

Final % B=100

Gradient Time=2 min

Flow Rate=5 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 9

Column: Phenomenex C18 10u 4.6×30 mm

Start % B=0

Final % B=100

Gradient Time=10 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=H₂O:ACN 95%:5% 10 mm Ammonium Acetate

Solvent B=H₂O:ACN 5%:95% 10 mm Ammonium Acetate

Condition 10

Column: Phenomenex 10u 3.0×50 mm

Start % B=0

Final % B=100

Gradient Time=3 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% methanol—90% H₂O—0.1% TFA

Solvent B=90% methanol—10% H₂O—0.1% TFA

Condition 11

Column: Xterra 4.6×30 mm S5

Start % B=0

Final % B=100

Gradient Time=2 min

Flow Rate=5 mL/Min

Wavelength=220

Solvent A=H₂O:ACN 95%:5% 10 mm Ammonium Acetate

Solvent B=H₂O:ACN 5%:95% 10 mm Ammonium Acetate

Compound F1 was prepared in analogous fashion to the procedure used tosynthesize 1a with following modification:(2S,5R)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acidwas used in place of N-Boc-L-proline.

Compound F2 was prepared in analogous fashion to the procedure used tosynthesize 1b.

Compound F3 was prepared in analogous fashion to the procedure used tosynthesize 1d.

Compound F4 was prepared in analogous fashion to the procedure used tosynthesize 1e.

Compound F5, F6 was prepared in analogous fashion to the procedure usedto synthesize example 1 from Compound F4.

Compound F7, F8 was prepared in analogous fashion to the procedure usedto synthesize F5 with following modification:(2S)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid wasused in place of(2S,5R)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid.

Retention time (LC- Condition); homogeneity index Entry Compound Name MSdata F1 RT = 3.838 minutes (condition 1, 94%); LRMS: Anal. Calcd. forC24H27BrN2O4 486.12; found: 487.26 (M + H)⁺. F2 RT = 3.175 minutes(condition 1, 83%); LRMS: Anal. Calcd. for C24H27BrN2O4 467.12; found:468.26 (M + H)⁺. F3 RT = 2.965 minutes (condition 1, 93%); LRMS: Anal.Calcd. for C42H48N6O4 700.37; found: 701.49 (M + H)⁺. F4 RT = 2.083minutes (condition 1, 98%); LRMS: Anal. Calcd. for C32H32N6 500.27;found: 501.40 (M + H)⁺. F5 RT = 1.222 minutes (condition 3, 98%); LRMS:Anal. Calcd. for C52H54N8O2 822.44; found: 823.5 (M + H)⁺. F6 methyl((1R)-2-((2R)-2-(5-(4′- RT = 1.512 minutes (condition(2-((2S,5R)-1-((2R)-2- 3, 98%); LRMS: Anal. Calcd.((methoxycarbonyl)amino)-2- for C52H50N8O6 882.39;phenylacetyl)-5-phenyl-2- found: 883.45 (M + H)⁺.pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate F7rel-(1R)-2-((2S)-2-(4-(4′-(2- RT = 1.223 minutes (condition((2S)-1-((2R)-2- 3, 98%); LRMS: Anal. Calcd. (dimethylamino)-2- forC50H56N8O2 800.45; phenylacetyl)octahydro-1H- found: 801.51 (M + H)⁺.indol-2-yl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2- oxo-1-phenylethanamine F8 methylrel-((1R)-2-((2S)-2-(4- RT = 1.513 minutes (condition(4′-(2-((2S)-1-((2R)-2- 3, 98%); LRMS: Anal. Calcd.((methoxycarbonyl)amino)-2- for C50H56N8O2 860.40;phenylacetyl)octahydro-1H- found: 861.42 (M + H)⁺.indol-2-yl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

Compound F9, F10, and F11 was prepared in analogous fashion to theprocedure used to synthesize Cap-3 first half procedure usingacetaldehyde, propionaldehyde, and butyraldehyde respectively.

Compound F12

(Boc)₂O (2.295 g, 10.20 mmol) was added to a mixture of compound F9 (1.0g, 4.636 mmol), hunig's base (1.78 mL, 10.20 mmol) in CH₂Cl₂ (12 mL),and the resulting mixture was stirred over night. The volatile componentwas removed in vacuo, and the residue was purified by a reverse phaseHPLC system (H₂O/methanol/TFA) to provide compound F12 as a clear wax(0.993 g).

LC (Cond. 3): RT=1.663 min; >95% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C15H21NO4: 279.33. found [M+Na]⁺ 302.30

Compound F13 was prepared in analogous fashion to the procedure used tosynthesized example 1 from Compound 1e and F12.

Compound F14 was prepared in analogous fashion to the procedure used tosynthesized 132e.

Compound F15, F16, and F17 was prepared in analogous fashion to theprocedure used to synthesize F14.

Retention time (LC-Condition); homogeneity Entry Compound Name index MSdata F9 RT = 0.580 minutes (condition 1, 94%); LRMS: Anal. Calcd. forC10H13NO2 179.09; found: 180.26 (M + H)⁺. F10 RT = 0.563 minutes(condition 3, 94%); LRMS: Anal. Calcd. for C11H15NO2 193.11; found:194.26 (M + H)⁺. F11 RT = 1.023 minutes (condition 3, 94%); LRMS: Anal.Calcd. for C12H17NO2 207.13; found: 208.31 (M + H)⁺. F12 RT = 1.663minutes (condition 3, 95%); LRMS: Anal. Calcd. for C15H21NO4 279.15;found: 302.30 (Na + H)⁺. F13 RT = 2.595 minutes (condition 4, 94%);LRMS: Anal. Calcd. for C56H66N8O6 946.51; found: 947.64 (M + H)⁺. F14(1R)—N-ethyl-2-((2S)-2-(4-(4′-(2- RT = 1.55 minutes (condition 5,((2S)-1-((2R)-2-(ethylamino)-2- 90%); LRMS: Anal. Calcd. forphenylacetyl)-2-pyrrolidinyl)- C46H50N8O2 746.41; found:1H-imidazol-5-yl)-4-biphenylyl)- 747.72 (M + H)⁺. 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethanamine F15(1R)—N-methyl-2-((2S)-2-(4-(4′- RT = 1.50 minutes (condition 5,(2-((2S)-1-((2R)-2- 94%); LRMS: Anal. Calcd. for(methylamino)-2-phenylacetyl)- C44H46N8O2 718.37; found:2-pyrrolidinyl)-1H-imidazol-5- 719.69 (M + H)⁺.yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine F16 N-((1R)-2-oxo-1-phenyl-2-((2S)- RT = 1.63 minutes(condition 5, 2-(4-(4′-(2-((2S)-1-((2R)-2- 90%); LRMS: Anal. Calcd. forphenyl-2-(propylamino)acetyl)- C48H54N8O2 774.43; found:2-pyrrolidinyl)-1H-imidazol-5- 775.76 (M + H)⁺.yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethyl)-1-propanamineF17 N-((1R)-2-((2S)-2-(4-(4′-(2-((2S)- RT = 1.81 minutes (condition 5,1-((2R)-2-(butylamino)-2- 85%); LRMS: Anal. Calcd. forphenylacetyl)-2-pyrrolidinyl)- C50H58N8O2 802.47; found:1H-imidazol-5-yl)-4-biphenylyl)- 803.79 (M + H)⁺. 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)- 1-butanamine

Compound F18 and F23 was prepared in analogous fashion to the procedureused to synthesize example 1 with following modification:N-Boc-L-alanine and N-Boc-L-valine was used in place of N-Boc-L-prolinerespectively.

Compound F22 was prepared in analogous fashion to the procedure used tosynthesize example 1 from Compound F19.

Compound F19, F24 was prepared in analogous fashion to the procedureused to synthesize 132e.

Compound F25 ethyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((ethoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

To a solution of F24 (0.06 g, 0.074 mmol) in DMF (1 mL) was addedHunig's base (0.105 mL, 0.593 mmol) and ethyl carbonochloridate (0.016mL, 0.163 mmol) then stirred it at room temperature. Two hours later,checked it by LCMS. There were three major peaks which indicated desiredcompound, tri-coupled, and tetra-coupled compound. Stopped reaction andconcentrated it by reduced pressure to get light brown oil which wastreated with 10 mL of 2 M NH₃ in methanol for 20 minutes thenconcentrated it again to a yellow solid which was purified bypreparative LC to provide compound F25 as a white TFA salt (57.6 mg).

LC (Cond. 6): RT=1.932 min, LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₅₄N₈₀₆:766.42. found 767.55.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.69-0.94 (m, 12H) 1.16 (t, J=7.02 Hz,6H) 1.90-2.26 (m, 8H) 2.40 (d, J=4.88 Hz, 2H) 3.73-3.92 (m, 4H)3.94-4.08 (m, 4H) 4.12 (t, J=7.78 Hz, 2H) 5.15 (t, J=7.02 Hz, 2H) 7.26(d, J=8.54 Hz, 2H) 7.85-7.93 (m, 4H) 7.93-8.01 (m, 4H) 8.13 (s, 2H)14.68 (s, 2H)

Compound F20, F21, and F26 was prepared in analogous fashion to theprocedure used to synthesize example 1.

Retention time (LC-Condition); Entry Compound Name homogeneity index MSdata F18 RT = 2.257 minutes (condition 5, 96%); LRMS: Anal. Calcd. forC42H54N8O6 766.42; found: 767.88 (M + H)⁺. F19 RT = 1.462 minutes(condition 5, 95%); LRMS: Anal. Calcd. for C32H38N8O2 566.31; found:567.79 (M + H)⁺. F20 propyl ((1S)-1-methyl-2-oxo-2- RT = 1.338 minutes(condition 3, ((2S)-2-(4-(4′-(2-((2S)-1-(N- 89%); LRMS: Anal. Calcd. for(propoxycarbonyl)-L-alanyl)-2- C40H50N8O6 738.39; found: 739.95 (M +H)⁺. pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate F21 butyl ((1S)-2-((2S)-2-(4-(4′-(2-RT = 1.447 minutes (condition 3, ((2S)-1-(N-(butoxycarbonyl)-L- 96%);LRMS: Anal. Calcd. for alanyl)-2-pyrrolidinyl)-1H- C42H54N8O6 766.93;found: imidazol-5-yl)-4-biphenylyl)- 768.02 (M + H)⁺.1H-imidazol-2-yl)-1-pyrrolidinyl)- 1-methyl-2-oxoethyl)carbamate F22(2S)-2-hydroxy-N-((1S)-2-((2S)- RT = 1.703 minutes (condition 4,2-(5-(4′-(2-((2S)-1-(N-((2S)-2- 98%); LRMS: Anal. Calcd. forhydroxy-3-methylbutanoyl)-L- C42H54N8O 766.93; found:alanyl)-2-pyrrolidinyl)-1H- 768.02 (M + H)⁺.imidazol-4-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)-3-methylbutanamide F23 RT = 2.881minutes (condition 7, 93%); LRMS: Anal. Calcd. for C46H62N8O6 822.48;found: 823.95 (M + H)⁺. F24 RT = 1.743 minutes (condition 7, 98%); LRMS:Anal. Calcd. for C36H46N8O2 622.37; found: 624.07 (M + H)⁺. F25 ethyl((1S)-1-(((2S)-2-(4-(4′-(2- RT = 1.932 minutes (condition 6,((2S)-1-((2S)-2- 97%); LRMS: Anal. Calcd. for ((ethoxycarbonyl)amino)-3-C42H54N8O6 766.42; found: methylbutanoyl)-2-pyrrolidinyl)- 767.55 (M +H)⁺. 1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate F26 isopropyl((1S)-1-(((2S)-2-(4-(4′- RT = 2.122 minutes (condition 6,(2-((2S)-1-((2S)-2- 98%); LRMS: Anal. Calcd. for((isopropoxycarbonyl)amino)-3- C44H58N8O6 794.45; found:methylbutanoyl)-2-pyrrolidinyl)- 795.58 (M + H)⁺. 1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Retention time (LC-Condition); homogeneity Entry Compound Name index MSdata F27 (2S)-1-((2S)-2-(4-(4′-(2-((2S)-1- RT = 1.03 minutes (condition3, ((2S)-2-hydroxypropanoyl)-2- 98%); LRMS: Anal. Calcd. forpyrrolidinyl)-1H-imidazol-5-yl)- C32H36N6O4 568.28; found:4-biphenylyl)-1H-imidazol-2-yl)- 569.76 (M + H)⁺.1-pyrrolidinyl)-1-oxo-2-propanol F28 tert-butyl ((1S)-1-(((2S)-2-(5-(4′-RT = 1.847 minutes (condition 3, (2-((2S)-1-((2S)-2-((tert- 95%); LRMS:Anal. Calcd. for butoxycarbonyl)(methyl)amino)- C50H70N8O6 878.54;found: 4-methylpentanoyl)-2- 879.53 (M + H)⁺.pyrrolidinyl)-1H-imidazol-4-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3- methylbutyl)methylcarbamate F29 tert-butyl((1S)-1-(((2S)-2-(5-(4′- RT = 2.202 minutes (condition 8,(2-((2S)-1-((2S)-2-((tert- 98%); LRMS: Anal. Calcd. forbutoxycarbonyl)(methyl)amino)- C50H70N8O6 878.54; found:3-methylpentanoyl)-2- 879.57 (M + H)⁺. pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2-methylbutyl)methylcarbamate F30 tert-butyl ((1S)-1-(((2S)-2-(5-(4′- RT =1.743 minutes (condition 8, (2-((2S)-1-((2S)-2-((tert- 96%); LRMS: Anal.Calcd. for butoxycarbonyl)(methyl)amino)- C48H66N8O6 850.51; found:3-methylbutanoyl)-2- 851.52 (M + H)⁺. pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2-methylpropyl)methylcarbamate F31 tert-butyl ((1S,2R)-1-(((2S)-2-(4- RT =1.82 minutes (condition 8, (4′-(2-((2S)-1-(N-(tert- 98%); LRMS: Anal.Calcd. for butoxycarbonyl)-N-methyl-L- C50H70N8O6 878.54; found:alloisoleucyl)-2-pyrrolidinyl)- 879.54 (M + H)⁺.1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylbutyl)methylcarbamate F32(2S)—N,4-dimethyl-1-((2S)-2-(4- RT = 3.715 minutes (condition 9,(4′-(2-((2S)-1-((2S)-4-methyl-2- 98%); LRMS: Anal. Calcd. for(methylamino)pentanoyl)-2- C40H54N8O2 678.44; found:pyrrolidinyl)-1H-imidazol-5-yl)- 679.46 (M + H)⁺.4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- pentanamineF33 (2S)—N,3-dimethyl-1-((2S)-2-(4- RT = 3.058 minutes (condition 9,(4′-(2-((2S)-1-((2S)-3-methyl-2- 99%); LRMS: Anal. Calcd. for(methylamino)pentanoyl)-2- C36H46N8O2 678.44; found:pyrrolidinyl)-1H-imidazol-5-yl)- 679.61 (M + H)⁺.4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- pentanamineF34 (2S)—N,3-dimethyl-1-((2S)-2-(4- RT = 3.206 minutes (condition 9,(4′-(2-((2S)-1-((2S)-3-methyl-2- 99%); LRMS: Anal. Calcd. for(methylamino)butanoyl)-2- C38H50N8O2 650.41; found:pyrrolidinyl)-1H-imidazol-5-yl)- 651.41 (M + H)⁺.4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- butanamine F35(2S,3R)-N,3-dimethyl-1-((2S)-2- RT = 3.43 minutes (condition 9,(4-(4′-(2-((2S)-1-((2S,3R)-3- 98%); LRMS: Anal. Calcd. for methyl-2-C40H54N8O2 678.44; found: (methylamino)pentanoyl)-2- 679.44 (M + H)⁺.pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2- pentanamine

Compound F27 to F31 was prepared in analogous fashion to the procedureused to synthesize example 1.

Compound F32 to F35 was prepared in analogous fashion to the procedureused to synthesize 1e.

Compound F36 was prepared in analogous fashion to the procedure used tosynthesize Cap-52.

Compound F37, F38, and F39 was prepared in analogous fashion to theprocedure used to synthesize example 1 from Compound F36 and LS16respectively.

Retention time (LC-Condition); Entry Compound homogeneity index MS dataF36 RT = 1.55 minutes (condition 10); LRMS: Anal. Calcd. for C10H13NO2189.1; found: 190.13 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.71-1.00(m, 6H) 1.16-1.41 (m, 3H) 1.75-2.09 (m, 1H) 3.39-3.64 (m, 3H) 7.13 (s,1H) 12.27 (s, 1H) F37 methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT =2.572 minutes (condition 1-((2S)-2-((methoxycarbonyl)amino)- 4, 98%);LRMS: Anal. Calcd. 2,3-dimethylbutanoyl)-2-pyrrolidinyl)- for C42H54N8O6766.42; 1H-imidazol-5-yl)-4-biphenylyl)-1H- found: 767.48 (M + H)⁺.imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1,2- dimethylpropyl)carbamateF38 methyl ((1S)-2-((2S)-2-(4-(4′-(2-((2S)- RT = 2.128 minutes(condition 1-((2S)-2-((methoxycarbonyl)amino)- 7, 98%); LRMS: Anal.Calcd. 2-(tetrahydro-2H-pyran-4-yl)acetyl)-2- for C44H54N8O8 822.41;pyrrolidinyl)-1H-imidazol-5-yl)-4- found: 823.45 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate F39 methyl (2-((2S)-2-(4-(4′-(2-((2S)-1- RT =2.162 minutes (condition (((methoxycarbonyl)amino)(tetrahydro- 7, 98%);LRMS: Anal. Calcd. 2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)- for1H-imidazol-5-yl)-4-biphenylyl)-1H- C44H54N8O8 822.42; found:imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- 823.49 (M + H)⁺.(tetrahydro-2H-pyran-4- yl)ethyl)carbamate

Compound F41 was prepared in analogous fashion to the procedure used tosynthesize example 1.

Compound F42 was prepared in analogous fashion to the procedure used tosynthesize 1e.

Retention time (LC-Condition); Entry Compound Name homogeneity index MSdata F40 RT = 2.72 minutes (condition 10); LRMS: Anal. Calcd. forC46H54N8O6 814.42; found: 815.98 (M + H)⁺. F41 methyl((1S)-2-((2S)-2-(4-(4′-(2- RT = 2.048 minutes (condition((2S)-1-((2R)-2-(ethylamino)-2- 10, 95%); LRMS: Anal.phenylacetyl)-2-pyrrolidinyl)- Calcd. for C41H46N8O41H-imidazol-5-yl)-4- 714.36; found: 715.84 biphenylyl)-1H-imidazol- (M +H)⁺. 2-yl)-1-pyrrolidinyl)-1-methyl- 2-oxoethyl)carbamate

Compound F42 was prepared in analogous fashion to the procedure used tosynthesize example 28f employing Cap-2 in place of Cap-4.

Compound F43 was prepared in analogous fashion to the procedure used tosynthesize 2 from Compound F42.

Retention time (LC-Condition); Entry Compound Name homogeneity index MSdata F42 RT = 2.0 minutes (condition 10, 95%); LRMS: Anal. Calcd. forC38H43N7O 613.35; found: 614.40 (M + H)⁺. F43 methyl((1S)-1-(((2S)-2-(5-(4′- RT = 2.308 minutes (condition 10,(2-((2S)-1-((2R)-2- 98%); LRMS: Anal. Calcd. for(diethylamino)-2-phenylacetyl)- C50H70N8O6 784.44; found:2-pyrrolidinyl)-1H-imidazol-4- 785.49 (M + H)⁺.yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-1,2-dimethylpropyl)carbamate

Compound F44 was prepared following below paper with followingmodification: glycine was used in place of leucine.

A simple method for preparation of N-mono- and N,N-di-alkylated α-aminoacids

Yuntao Song et al., Tetrahedron Lett. 41, October 2000, Pages 8225-8230.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37-1.62 (m, 2H) 1.86 (dd, J=12.36,1.98 Hz, 2H) 3.01-3.12 (m, 1H) 3.15 (s, 2H) 3.25 (t, J=11.75 Hz, 2H)3.86 (dd, J=11.44, 4.12 Hz, 2H) 7.67-8.48 (m, 1H).

Compound F45

2-(tetrahydro-2H-pyran-4-ylamino)acetic acid (0.2 g, 1.256 mmol) F44 wasdissolved in DMF (22.5 mL) and Et₃N (2.5 mL, 17.94 mmol). After 5minutes BOC₂O (0.583 mL, 2.51 mmol) was added and the reaction solutionwas heated to 60° C. for 1 h. The reaction was concentrated by reducedpressure providing a light yellow oil to which was added 20 mL HCl H₂Owhich was adjusted to PH3 at 0° C. and stirred for 10 minutes. Thereaction mixture was extracted by ethyl acetate 3×20 mL, dried (MgSO₄),filtered, and concentrated to dryness. Ether was added and the mixturewas sonicated and filtered providing a white solid F452-(tert-butoxycarbonyl(tetrahydro-2H-pyran-4-yl)amino)acetic acid (0.14g, 0.540 mmol, 43.0% yield).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.27-1.44 (m, 9H) 1.43-1.69 (m, 4H)3.19-3.39 (m, 2H) 3.74 (s, 2H) 3.79-3.92 (m, 2H) 3.97-4.16 (m, 1H) 12.46(s, 1H).

Compound F46 was prepared following the below referenced procedure withfollowing modification: (S)-tert-butyl 2-amino-3-methylbutanoate wasused in place of (S)-methyl2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylbutanoate.

Hans-Joachim Knolker, et al. Synlett 1997; 925-928

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.77-0.97 (m, 6H) 1.32-1.45 (m, 9H)1.45-1.56 (m, 2H) 1.74-1.91 (m, 2H) 1.94-2.11 (m, 1H) 3.36-3.53 (m, 2H)3.76 (dd, J=8.09, 6.26 Hz, 1H) 3.77-3.90 (m, 2H) 4.69 (dd, J=9.00, 4.73Hz, 1H) 7.35 (d, J=8.24 Hz, 1H)

Compound F47

To a Compound 46 (S)-tert-butyl3-methyl-2-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)butanoate (0.21g, 0.697 mmol) was added HCl in dioxane (15 mL, 60.0 mmol) and themixture was stirred at room temperature under nitrogen for three hours.The reaction was done and concentrated under reduced pressure to provideF47(S)-3-methyl-2-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)butanoicacid (0.1694 g, 0.691 mmol, 100% yield) as a clear wax.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t, J=6.71 Hz, 6H) 1.41-1.60 (m,2H) 1.85 (d, J=12.21 Hz, 2H) 1.97-2.08 (m, 1H) 3.41 (t, J=10.68 Hz, 1H)3.45-3.52 (m, 1H) 3.64-3.74 (m, 1H) 3.77-3.89 (m, 2H) 4.63-4.72 (m, 1H)7.32 (d, J=8.55 Hz, 1H) 12.52 (s, 1H)

Compound F48 to F58 except F51 was prepared in analogous fashion to theprocedure used to synthesize example 1 from LS18.

Compound F51 was prepared in analogous fashion to the procedure used tosynthesize 1e from F50.

Retention time (LC-Condition); homogeneity Entry Compound Name index MSdata F48 methyl ((1S)-2-methyl-1-(((2S)-2-(4- RT = 2.103 minutes(condition (4′-(2-((2S)-1-(N-(tetrahydro-2H- 7, 98%); LRMS: Anal. Calcd.pyran-4-yl)-L-alanyl)-2-pyrrolidinyl)- for C41H52N8O5 736.41;1H-imidazol-4-yl)-4-biphenylyl)-1H- found: 737.07 (M + H)⁺.imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl)carbamate F49 methyl((1S)-2-methyl-1-(((2S)-2-(4- RT = 2.117 minutes (condition(4′-(2-((2S)-1-(N-(tetrahydro-2H- 7, 98%); LRMS: Anal. Calcd.pyran-4-yl)-L-valyl)-2-pyrrolidinyl)- for C43H56N8O5 764.44;1H-imidazol-4-yl)-4-biphenylyl)-1H- found: 765.75 (M + H)⁺.imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)propyl)carbamate F50 RT = 2.547minutes (condition 7, 98%); LRMS: Anal. Calcd. for C45H58N8O7 822.44;found: 823.17 (M + H)⁺. F51 methyl ((1S)-2-methyl-1-(((2S)-2-(4- RT =2.138 minutes (condition (4′-(2-((2S)-1-(N-(tetrahydro-2H- 7, 96%);LRMS: Anal. Calcd. for pyran-4-yl)glycyl)-2-pyrrolidinyl)-1H- C40H50N8O5722.39; found: imidazol-4-yl)-4-biphenylyl)-1H- 723.63 (M + H)⁺.imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl)carbamate F52 methyl((1S)-2-methyl-1-(((2S)-2-(4- RT = 2.083 minutes (condition(4′-(2-((2S)-1-(N-(tetrahydro-2H- 7, 98%); LRMS: Anal. Calcd.pyran-4-yl)-D-valyl)-2-pyrrolidinyl)- for C43H56N8O5 764.44;1H-imidazol-4-yl)-4-biphenylyl)-1H- found: 765.78 (M + H)⁺.imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl)carbamate F53 methyl((1S)-2-methyl-1-(((2S)-2-(4- RT = 0.963 minutes (condition(4′-(2-((2S)-1-(N-(tetrahydro-2H- 11, 95%); LRMS: Anal. Calcd.pyran-4-yl)-D-alanyl)-2-pyrrolidinyl)- for C43H54N8O7 736.41;1H-imidazol-4-yl)-4-biphenylyl)-1H- found: 737.54 (M + H)⁺.imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl)carbamate F54(3S)-tetrahydro-3-furanyl ((1S)-1- RT = 2.378 minutes (condition(((2S)-2-(4-(4′-(2-((2S)-1-(N- 7, 95%); LRMS: Anal. Calcd.(methoxycarbonyl)-L-valyl)-2- for C43H54N8O7 794.41;pyrrolidinyl)-1H-imidazol-4-yl)-4- found: 795.94 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate F55 tetrahydro-2H-pyran-4-yl ((1S)-1- RT = 2.447minutes (condition (((2S)-2-(4-(4′-(2-((2S)-1-(N- 7, 99%); LRMS: Anal.Calcd. (methoxycarbonyl)-L-valyl)-2- for C44H56N8O7 808.43;pyrrolidinyl)-1H-imidazol-4-yl)-4- found: 809.42 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate F56 (3R)-tetrahydro-3-furanyl ((1S)-1- RT = 2.398minutes (condition (((2S)-2-(4-(4′-(2-((2S)-1-(N- 7, 96%); LRMS: Anal.Calcd. (methoxycarbonyl)-L-valyl)-2- for C43H54N8O7 794.41;pyrrolidinyl)-1H-imidazol-4-yl)-4- found: 795.36 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate F57 methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT =2.272 minutes (condition 1-((2R)-2-((methoxycarbonyl)amino)- 7, 98%);LRMS: Anal. Calcd. 2-(tetrahydro-2H-pyran-4-yl)acetyl)-2- for C42H52N8O7780.40; pyrrolidinyl)-1H-imidazol-5-yl)-4- found: 781.34 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate F58 methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT =2.225 minutes (condition 1-((2S)-2-((methoxycarbonyl)amino)- 7, 98%);LRMS: Anal. Calcd. 2-(tetrahydro-2H-pyran-4-yl)acetyl)-2- for C42H52N8O7780.40; pyrrolidinyl)-1H-imidazol-5-yl)-4- found: 781.27 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Compound F59

Compound F59 was prepared in analogous fashion to the procedure used tosynthesize 26a with following modification: Boc-L-val-OH was used inplace of Boc-D-val-OH.

Compound F60 to F62 were prepared in analogous fashion to the procedureused to synthesize example 29 from F59.

Compound F63 and F64 were prepared in analogous fashion to the procedureused to synthesized Cap45.

Retention time (LC-Condition); Entry Compound Name homogeneity index MSdata F59 RT = 1.743 minutes (condition 7, 98%); LRMS: Anal. Calcd. forC36H46N8O2 622.37; found: 624.07 (M + H)⁺. F60N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1- RT = 2.047 minutes (condition((2S)-2-acetamido-3-methylbutanoyl)-2- 10, 98%); LRMS: Anal.pyrrolidinyl)-1H-imidazol-4-yl)-4- Calcd. for C40H50N8O4biphenylyl)-1H-imidazol-2-yl)-1- 706.44; found: 707.77 (M + H)⁺.pyrrolidinyl)carbonyl)-2- methylpropyl)acetamide F61N-((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2- RT = 2.215 minutes (condition((2S)-1-((2S)-3-methyl-2- 10 98%); LRMS: Anal.(propionylamino)butanoyl)-2- Calcd. for C42H54N8O4pyrrolidinyl)-1H-imidazol-4-yl)-4- 734.43; found: 735.87 (M + H)⁺.biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)propanamide F622-methoxy-N-((1S)-1-(((2S)-2-(4-(4′-(2- RT = 2.232 minutes (condition((2S)-1-((2S)-2-((methoxyacetyl)amino)- 10, 99%); LRMS: Anal.3-methylbutanoyl)-2-pyrrolidinyl)-1H- Calcd. forimidazol-4-yl)-4-biphenylyl)-1H- C42H54N8O6 766.93; found: 768.05imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- (M + H)⁺.methylpropyl)acetamide F63 1-methyl-3-((1S)-2-methyl-1-(((2S)-2-(4- RT =2.082 minutes (condition (4′-(2-((2S)-1-(N-(methylcarbamoyl)-L- 10,95%); LRMS: Anal. valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)- Calcd. forC40H52N10O4 4-biphenylyl)-1H-imidazol-2-yl)-1- 736.42; found:pyrrolidinyl)carbonyl)propyl)urea 737.86 (M + H)⁺. F641-ethyl-3-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT = 1.617 minutes(condition 1-((2S)-2-((ethylcarbamoyl)amino)-3- 12, 93%); LRMS: Anal.methylbutanoyl)-2-pyrrolidinyl)-1H- Calcd. for C42H56N10O4imidazol-4-yl)-4-biphenylyl)-1H- 764.45; found:imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- 765.57 (M + H)⁺.methylpropyl)urea

Compound F65

To a solution of F59 (0.06 g, 0.074 mmol in DMF (1 mL) was addeddimethylsulfamoyl chloride (0.016 mL, 0.148 mmol) and Hunig's Base(0.078 mL, 0.445 mmol) then stirred it at room temperature for 3 h.Solvent was removed by reduced pressure to get light brown oil which waspurified by PreHPLC providing F65N—((S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-(N,N-dimethylsulfamoylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)propane-2-sulfonamide(19.0 mg, 0.018 mmol, 24.08% yield)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.65-1.03 (m, 12H) 1.87-2.08 (m, 4H)2.06-2.27 (m, 4H) 2.37-2.46 (m, 2H) 2.56-2.69 (m, 12H) 3.66-3.92 (m, 6H)5.14 (t, J=7.63 Hz, 2H) 7.49 (d, J=9.16 Hz, 2H) 7.89 (d, J=8.24 Hz, 4H)7.96 (s, 4H) 8.14 (s, 2H) 14.72 (s, 2H)

RT=2.047 minutes (condition 10, 98%); LRMS: Anal. Calcd. for C₄₀H₅₀N₈O₄706.38. found: 707.77 (M+H)⁺.

1b Fret (EC50,uM)=0.21

Compound F66 to F69 was prepared in analogous fashion to the procedureused to synthesize F65 from Compound F59.

Retention time (LC- Condition); homogeneity Entry Compound Name index MSdata F66 N-((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1- RT = 2.02minutes ((2S)-3-methyl-2- (condition 10, 98%); LRMS:((methylsulfonyl)amino)butanoyl)-2- Anal. Calcd. forpyrrolidinyl)-1H-imidazol-4-yl)-4- C38H50N8O6S2 778.38;biphenylyl)-1H-imidazol-2-yl)-1- found: 779.60 (M + H)⁺.pyrrolidinyl)carbonyl)propyl)methanesulfonamide F67N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2- RT = 2.172 minutes((ethylsulfonyl)amino)-3-methylbutanoyl)-2- (condition 10 98%); LRMS:pyrrolidinyl)-1H-imidazol-4-yl)-4- Anal. Calcd. forbiphenylyl)-1H-imidazol-2-yl)-1- C40H54N8O6S2 807.04;pyrrolidinyl)carbonyl)-2- found: 808.42 (M + H)⁺.methylpropyl)ethanesulfonamide F68N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2- RT = 2.217 minutes((cyclopropylsulfonyl)amino)-3- (condition 10, 93%); LRMS:methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol- Anal. Calcd. for4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- C42H54N8O6S2 831.06;pyrrolidinyl)carbonyl)-2- found: 832.49 (M + H)⁺.methylpropyl)cyclopropanesulfonamide F69N-((1S)-1-methyl-2-((2S)-2-(5-(4′-(2-((2S)-1- RT = 1.983 minutes(N-(methylsulfonyl)-L-alanyl)-2-pyrrolidinyl)- (condition 10, 95%);LRMS: 1H-imidazol-4-yl)-4-biphenylyl)-1H- Anal. Calcd. forimidazol-2-yl)-1-pyrrolidinyl)-2- C34H42N8O6S2 722.27;oxoethyl)methanesulfonamide found: 723.68 (M + H)⁺.

Compound F70 was prepared following the procedure described in AnnaHelms et al., J. Am. Chem. Soc. 1992 114(15) pp 6227-6238.

Compound F71 was prepared in analogous fashion to the procedure used tosynthesize Example 1.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.69-0.95 (m, 12H) 1.92 (s, 12H)1.97-2.27 (m, 8H) 2.40 (s, 2H) 3.55 (s, 6H) 3.73-3.97 (m, 4H) 4.12 (t,J=7.78 Hz, 2H) 5.14 (t, J=7.02 Hz, 2H) 7.34 (d, J=8.24 Hz, 2H) 7.49-7.70(m, 4H) 8.04 (s, 2H) 14.59 (s, 2H) RT=2.523 minutes (condition 7, 96%);LRMS: Anal. Calcd. for C₄₄H₅₈N₈O₆ 794.45. found: 795.48 (M+H)⁺.

Section cj Synthesis of Carbamate Replacements Example cj-2 and cj-3

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-2)

To a solution of (S)-tert-butyl2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-1) (1.00 g, 1.91 mmol), iPr₂NEt (1.60 mL, 9.19 mmol) and N—Z-valine(0.62 g, 2.47 mmol) in DMF (10 mL) was added HATU (0.92 g, 2.42 mmol).The solution was allowed to stir at rt for 1 h and then it was pouredinto ice water (ca. 250 mL) and allowed to stand for 20 min. The mixturewas filtered and the solid washed with water and then dried in vacuoovernight to afford a colorless solid (1.78 g) which was used as such inthe next step. LCMS: Anal. Calcd. for C₄₄H₅₁N₇O₅: 757. found: 758(M+H)⁺. A mixture of this material (1.70 g) and 10% Pd—C (0.37 g) inMeOH (100 mL) was hydrogenated (balloon pressure) for 12 h. The mixturewas then filtered and the solvent removed in vacuo. The residue waspurified by silica gel chromatography (Biotage system/0-10% MeOH—CH₂Cl₂)to afford the title compound as a light yellow foam (0.90 g, 76%).

¹HNMR (400 MHz, DMSO-d₆) δ 12.18 (s, 0.35H), 11.73 (s, 0.65H), 11.89 (s,0.65H), 11.82 (s, 0.35H), 7.77-7.81 (m, 3H), 7.57-7.71 (m, 5H),7.50-7.52 (m, 2H), 5.17 (dd, J=3.6, 6.5 Hz, 0.3H), 5.08 (dd, J=3.6, 6.5Hz, 0.7H), 4.84 (m, 0.3H), 4.76 (m, 0.7H), 3.67-3.69 (m, 1H), 3.50-3.62(m, 1H), 3.34-3.47 (m, 2H), 2.22-2.28 (m, 2H), 2.10-2.17 (m, 2H),1.74-2.05 (m, 6H), 1.40 (s, 4H), 1.15 (s, 5H), 0.85-0.91 (m, 4H), 0.79(d, J=6.5 Hz, 2H).

LCMS: Anal. Calcd. for C₃₆H₄₅N₇O₃: 623. found: 624 (M+H)⁺.

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((R)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-3)

(S)-tert-Butyl2-(5-(4′-(2-((S)-1-((R)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-3) was prepared using the same method used to prepare cj-2 to give acolorless foam (1.15 g, 76%). ¹HNMR (400 MHz, DMSO-d₆) δ 12.17 (s,0.35H), 12.04 (s, 0.65H), 11.89 (s, 0.65H), 11.81 (s, 0.35H), 7.78-7.83(m, 3H), 7.60-7.71 (m, 5H), 7.43-7.52 (m, 2H), 5.22-5.25 (m, 0.4H),5.05-5.07 (m, 0.6H), 4.83-4.86 (m, 0.5H), 4.72-4.78 (m, 0.5H), 3.78-3.84(m, 1H), 3.49-3.64 (m, 2H), 3.35-3.43 (m, 2H), 2.19-2.32 (m, 1H),2.04-2.17 (m, 3H), 1.95-2.04 (m, 2H), 1.76-1.90 (m, 3H), 1.40 (s, 4H),1.15 (s, 5H), 0.85-0.91 (m, 4H), 0.67 (d, J=6.5 Hz, 1H), 0.35 (d, J=6.5Hz, 1H). LCMS: Anal. Calcd. for C₃₆H₄₅N₇O₃: 623. found: 624 (M+H)⁺.

Example cj-4 and cj-5

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(pyrimidin-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-4)

A mixture of (S)-tert-butyl2-(5-(4′-(2-((S)-1-((s)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-2) (0.45 g, 0.72 mmol), 2-bromopyrimidine (0.37 g, 2.34 mmol) andiPr₂NEt (0.20 mL, 1.18 mmol) in toluene-DMSO (4:1, 5 mL) was heated at90° C. overnight. The volatiles were removed in vacuo and the residuewas purified by preparative HPLC (YMC Pack C-1 8, 30×100mm/MeCN—H₂O-TFA). The title compound (0.56 g, 74%), as its TFA salt, wasobtained as a yellow-orange glass.

¹HNMR (400 MHz, DMSO-d₆) δ 14.56 (br s, 2H), 8.28 (d, J=5.0 Hz, 1H),8.12-8.20 (m, 2H), 7.94-7.97 (m, 3H), 7.83-7.91 (m, 5H), 7.06 (d, J=8.1Hz, 1H), 6.62 (app t, J=5.0 Hz, 1H), 4.99-5.10 (m, 2H), 4.50 (app t,J=7.7 Hz, 1H), 4.07-4.12 (m, 2H), 3.83-3.87 (m, 1H), 3.56-3.62 (m, 1H),3.40-3.47 (m, 2H), 2.36-2.41 (m, 1H), 1.94-2.22 (m, 6H), 1.40 (s, 4H),1.17 (s, 5H), 0.88 (app t, J=6.5 Hz, 6H).

LCMS: Anal. Calcd. for C₄₀H₄₇N₉O₃: 701. found: 702 (M+H)⁺.

Preparation of(S)-tert-Butyl-2-(5-(4′-(2-((S)-1-((R)-3-methyl-2-(pyrimidin-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-5)

The TFA salt of the title compound was prepared following the samemethod used to prepare cj-4 to give a light yellow solid (0.375 g, 59%).

¹HNMR (400 MHz, DMSO-d₆) δ 14.67 (br s, 2H), 8.30 (d, J=4.3 Hz, 1H),8.04-8.19 (m, 2H), 7.84-7.96 (m, 8H), 6.88 (d, J=8.6 Hz, 1H), 6.61 (appt, J=4.5 Hz, 1H), 5.17 (dd, J=4.4, 8.0 Hz, 1H), 5.00-5.07 (m, 1H), 4.67(dd, J=7.3, 8.1 Hz, 1H), 3.91-3.96 (m, 1H), 3.70-3.75 (m, 1H), 3.56-3.62(m, 1H), 3.42-3.45 (m, 1H), 2.39-2.43 (m, 2H), 2.04-2.16 (m, 5H),1.94-1.97 (m, 2H), 1.40 (s, 4H), 1.17 (s, 5H), 0.95 (d, J=6.6 Hz, 2.5H),0.91 (d, J=6.6 Hz, 2.5H), 0.86 (d, J=6.6 Hz, 0.5H), 0.81 (d, J=6.6 Hz,0.5H).

LCMS: Anal. Calcd. for C₄₀H₄₇N₉O₃: 701. found: 702 (M+H)⁺.

Example cj-6 and cj-7

Preparation of 1-Methyl-2-(methylthio)-4,5-dihydro-1H-imidazolehydroiodide

The title compound was prepared according to: Kister, J.; Assef, G.;Dou, H. J.-M.; Metzger, J. Tetrahedron 1976, 32, 1395. Thus, a solutionof N-methylethylenediamine (10.8 g, 146 mmol) in EtOH—H₂O (1:1, 90 mL)was preheated to 60° C. and CS₂ (9.0 mL, 150 mmol) was added dropwise.The resulting mixture was heated at 60° C. for 3 h and then conc. HCl(4.7 mL) was slowly added. The temperature was raised to 90° C. andstirring was continued for 6 h. After the cooled mixture had been storedat −20° C., it was filtered and the resulting solid dried in vacuo toafford 1-methylimidazolidine-2-thione (8.43 g, 50%) as a beige solid.

¹HNMR (400 MHz, CDCl₃) δ 5.15 (s, br, 1H), 3.67-3.70 (m, 2H), 3.53-3.58(m, 2H), 3.11 (s, 3H).

To a suspension of 1-methylimidazolidine-2-thione (5.17 g, 44.5 mmol) inacetone (50 mL) was added MeI (2.9 mL, 46.6 mmol). The solution wasallowed to stir at room temperature for 4 h and the resulting solid wasquickly filtered and then dried in vacuo to give1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (8.79 g,77%) as beige solid.

¹HNMR (400 MHz, CDCl₃) δ 9.83 (s, br, 1H), 3.99-4.12 (m, 4H), 3.10 (s,3H), 2.99 (s, 3H).

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(1-methyl-4-5-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-6)

A mixture of (S)-tert-butyl2-(5-(4′-(2-((S)-1-((s)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-pyrrolidine-1-carboxylate(cj-2) (0.280 g, 0.448 mmol) and1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (cj-3a)(0.121 g, 0.468 mmol) in CH₃CN (5 mL) was heated at 90° C. for 12 h.Another 0.030 g of 1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazolehydroiodide (cj-3a) was added and heating continued for a further 12 h.The crude reaction mixture was directly purified by prep HPLC (Luna C—18/MeCN—H₂O-TFA) to give the TFA salt of the title compound (0.089 g) asa light yellow solid which was used as such in the subsequent steps.

LCMS: Anal. Calcd. for C₄₀H₅₁N₉O₃: 705. found: 706 (M+H)⁺.

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((R)-3-methyl-2-(1-methyl-4-5-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-7)

The title compound was prepared from cj-3 according to the methoddescribed for the synthesis of cj-6, except that the reaction mixturewas initially purified by prep HPLC (YMC-Pack 25×250 mm/MeCN—H₂O—NH₄OAc)and then repurified by prep HPLC (Luna Phenyl-hexyl/MeCN—H₂O—NH₄OAc).This gave the desired product (0.005 g) as a foam which was used as suchin the subsequent steps.

LCMS: Anal. Calcd. for C₄₀H₅₁N₉O₃: 705. found: 706 (M+H)⁺.

Example cj-8 and cj-9

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(3,4-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-8)

A mixture of (s)-tert-butyl2-(5-(4′-(2-((S)-1-((s)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-2) (0.298 g, 0.480 mmol), 4,5-dihydro-1H-imidazole-2-sulfonic acid(AstaTech) (0.090 g, 0.60 mmol) and iPr₂NEt (0.083 mL, 0.48 mmol) inEtOH (4 mL) was heated at 100° C. for 12 h. The cooled mixture wasevaporated to dryness and the residue was purified by prep HPLC (Luna 5uC18/MeCN—H₂O-TFA, ×2) to afford the TFA salt of the title compound(0.390 g, 73%) as a light yellow solid.

¹HNMR (400 MHz, DMSO-d₆) δ 14.66 (br s, 2H), 8.51 (br s, 1H), 8.20 (d,J=10.1 Hz, 2H), 8.10 (br s, 1H), 7.82-7.91 (m, 7H), 7.30 (br s, 1H),5.12 (t, J=7.1 Hz, 1H), 4.97-5.05 (m, 2H), 4.37 (dd, J=4.3, 10.1 Hz,2H), 3.82-3.86 (m, 2H), 3.73-3.77 (m, 2H), 3.59 (s, 4H), 3.39-3.48 (m,2H), 2.15-2.25 (m, 2H), 1.93-2.07 (m, 5H), 1.40 (s, 4H), 1.17 (s, 5H),0.93 (d, J=6.6 Hz, 3H), 0.69 (br s, 3H).

LCMS: Anal. Calcd. for C₃₉H₄₉N₉O₃: 691. found: 692 (M+H)⁺.

Preparation of (S)-tert-Butyl2-(5-(4′-(2-((S)-1-((R)-3-methyl-2-(3,4-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-9)

The title compound was prepared from cj-3 according to the same methodused to prepare cj-8 to afford the TFA salt (0.199 g, 57%) as a yellowglass.

¹HNMR (400 MHz, DMSO-d₆) δ 14.58 (br s, 4H), 8.23 (d, J=9.6 Hz, 1H),8.11 (s, 1H), 7.87-7.89 (m, 6H), 7.25 (br s, 1H), 5.17-5.20 (m, 1H),4.96-5.04 (m, 1H), 4.37 (dd, J=5.5, 9.6 Hz, 1H), 3.91-3.95 (m, 2H),3.37-3.46 (m, partially obscured by H₂O, 4H), 2.39-2.42 (m, partiallyobscured by solvent, 2H), 2.01-2.09 (m, 4H), 1.94-1.98 (m, 2H), 1.40 (s,3H), 1.17 (s, 6H), 0.95 (d, J=6.5 Hz, 2.5H), 0.85 (d, J=6.5 Hz, 2.5H),0.66 (d, J=7.0 Hz, 0.5H), 0.54 (d, J=6.5 Hz, 0.5H).

LCMS: Anal. Calcd. for C₃₉H₄₉N₉O₃: 691. found: 692 (M+H)⁺.

Example cj-1

Preparation of(S)-3-Methyl-2-(pyrimidin-2-ylamino)-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-1-one(cj-10a)

Step 1: A solution of the TFA salt of (S)-tert-butyl2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(pyrimidin-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(cj-4) (0.208 g, 0.199 mmol) in a mixture CH₂Cl₂ (4 mL) and TFA (3 mL)was stirred at room temperature for 1.5 h. The solvents were thenremoved in vacuo and the residue was purified by prep HPLC (Luna 5uC18/MeCN—H₂O-TFA) to give the TFA salt of the title compound (0.391 g)as an orange gum.

¹HNMR (400 MHz, DMSO-d₆) δ 14.53 (br s, 3H), 9.52-9.57 (m, 2H),8.98-9.04 (m, 2H), 8.28 (d, J=4.6 Hz, 2H), 8.13 (br s, 1H), 7.79-7.91(m, 7H), 7.07 (d, J=8.1 Hz, 1H), 6.62 (app t, J=4.8 Hz, 1H), 5.07 (t,J=7.1 Hz, 1H), 4.72-4.78 (m, 2H), 4.48-4.51 (m, 1H), 4.08-4.12 (m, 2H),3.28-3.36 (m, 2H), 2.37-2.42 (m, 2H), 1.97-2.22 (m, 6H), 0.88 (app t,J=4.5 Hz, 6H).

LCMS: Anal. Calcd. for C₃₅H₃₉N₉O: 601. found: 602 (M+H)⁺.

Similarly, the following examples were prepared according to therepresentative method above;

Example Structure LCMS cj-10a (from cj-3)

LCMS: Anal. Calcd. for C₃₅H₃₉N₉O: 601; found: 602 (M + H)⁺. cj-10b (fromcj-2)

LCMS: Anal. Calcd. for C₃₅H₄₃N₉O: 605; found: 606 (M + H)⁺. cj-10c (fromcj-3)

LCMS: Anal. Calcd. for C₃₅H₄₃N₉O: 605; found: 606 (M + H)⁺. cj-10d (fromcj-2)

LCMS: Anal. Calcd. for C₃₄H₄₁N₉O: 591; found: 592 (M + H)⁺. cj-10e (fromcj-3)

LCMS: Anal. Calcd. for C₃₄H₄₁N₉O: 591; found: 592 (M + H)⁺.

Preparation of methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate(cj-11)

methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

Step 2: To a solution of the TFA salt of(S)-3-methyl-2-(pyrimidin-2-ylamino)-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-1-one(cj-10) (0.208 g, 0.197 mmol) in DMF (4 mL) was added iPr₂NEt (0.20 mL,1.15 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.049 g,0.28 mmol) and HATU (0.105 g, 0.276 mmol). The solution was stirred for1.5 h at room temperature, diluted with MeOH (2 mL) and purifieddirectly by prep HPLC (Luna 5u C18/MeCN—H₂O—NH₄OAc). This material wasrepurified by flash chromatography (SiO₂/2-10% MeOH—CH₂Cl₂) to give asolid which was lyophilized from CH₃CN—H₂O to give the title compound(48.6 mg, 32%) as a colourless solid.

¹HNMR (400 MHz, DMSO-d₆) δ 11.78 (br s, 1H), 8.28 (d, J=4.5 Hz, 1H),7.76-7.79 (m, 4H), 7.66-7.69 (m, 4H), 7.48-7.51 (m, 2H), 7.29 (d, J=8.6Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.60 (app t, J=4.5 Hz, 1H), 5.03-5.09(m, 2H), 4.48 (t. J=8.1 Hz, 1H), 3.99-4.08 (m, 2H), 3.78-3.85 (m, 2H)3.53 (s, 3H), 2.12-2.21 (m, 4H), 1.87-2.05 (m, 7H), 0.83-0.97 (m, 12H).

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₄: 758. found: 759 (M+H)⁺.

Similarly, the following examples were prepared according to therepresentative method above;

Compound Example Name Structure LCMS cj-11a (from cj-10 and Cap-52)methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N-2-pyrimidinyl-L- valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₀H₄₆N₁₀O₄: 730; found: 731 (M + H)⁺. cj-11b(from cj-10 and Cap-4) methyl ((1R)-2- oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-(N-2- pyrimidinyl-L- valyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₅H₄₈N₁₀O₄: 792; found: 793 (M + H)⁺. cj-11c(from cj-10 and Cap-2) N-((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) carbonyl)-2-methylpropyl)- 2- pyrimidinamine

LCMS: Anal. Calcd. for C₄₇H₅₄N₁₀O₂: 790; found: 791 (M + H)⁺. cj-11d(from cj-10b and Cap-51) methyl ((1S)-2- methyl-1-(((2S)- 2-(5-(4′-(2-((2S)-1-(N-(1- methyl-4,5- dihydro-1H- imidazol-2-yl)- L-valyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1-pyrrolidinyl) carbonyl)propyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₄N₁₀O₄: 762; found: 763 (M + H)⁺. cj-11e(from cj-10d and Cap-51) methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-(N-(4,5-dihydro- 1H-imidazol-2- yl)-L-valyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl)carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₅₂N₁₀O₄: 748; found: 749 (M + H)⁺. cj-11f(from cj-10d and Cap-52) methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N-(4,5-dihydro- 1H-imidazol-2- yl)-L-valyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl)-1-methyl-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₃₉H₄₈N₁₀O₄: 720; found: 721 (M + H)⁺. cj-11g(from cj-10d and Cap-2) N-((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) carbonyl)-2-methylpropyl)- 4,5-dihydro-1H- imidazol-2- amine

LCMS: Anal. Calcd. for C₄₆H₅₆N₁₀O₂: 780; found: 781 (M + H)⁺. cj11h(from cj-10d and Cap-4) methyl ((1R)-2- oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-(N-2- pyrimidinyl-D- valyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) ethyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₅₀N₁₀O₄: 782; found: 783 (M + H)⁺. cj-11i(from cj-10a and Cap-51) methyl ((1S)-2- methyl-1-(((2S)- 2-(5-(4′-(2-((2S)-1-(N-2- pyrimidinyl-D- valyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) carbonyl)propyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₄: 758; found: 759 (M + H)⁺. cj-11j(from cj-10a and Cap-52) methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1-(N-2- pyrimidinyl-D- valyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl) ethyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₄₆N₁₀O₄: 730; found: 731 (M + H)⁺. cj-11k(from cj-10a and Cap-2) N-((1R)-1- (((2S)-2-(5-(4′- 2-((2S)-1-((2R)- 2-(diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazaol-2-yl)- 1- pyrrolidinyl) carbonyl)-2-methylpropyl)- 2- pyrimidinamine

LCMS: Anal. Calcd. for C₄₇H₅₄N₁₀O₂: 790; found: 791 (M + H)⁺. cj-11l(from cj-10a and Cap-4)

LCMS: Anal. Calcd. for C₄₅H₄₈N₁₀O₄: 792; found: 793 (M + H)⁺. cf-11m(from cj-10c and Cap-51) methyl ((1S)-2- methyl-1-(((2S)- 2-(5-(4′-(2-((2S)-1-(N-(1- methyl-4,5- dihydro-1H- imidazol-2-yl)- D-valyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1-pyrrolidinyl) carbonyl) propyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₄N₁₀O₄: 762; found: 763 (M + H)⁺. cj-11n(from cj-10e and Cap-51) methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-(N-(4,5-dihydro- 1H-imidazol-2- yl)-D-valyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl)carbonyl)-2- methyl)propyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₅₂N₁₀O₄: 748; found: 749 (M + H)⁺. cj-11o(from cj-10e and Cap- 54b) methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(4′- (2-((2S)-1-(N- (4,5-dihydro- 1H-imidazol-2-yl)-D-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)- 2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₅₀N₁₀O₄: 746; found: 747 (M + H)⁺. cj-11p(from cj-10e and Cap-2) N-((1R)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)- 1- pyrrrolidinyl) carbonyl)-2-methylpropyl)- 4,5-dihydro-1H- imidazol-2- amine

LCMS: Anal. Calcd. for C₄₆H₅₆N₁₀O₂: 780; found: 781 (M + H)⁺.

Example-cj-13

Preparation of Methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-13)

To a solution of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(cj-12) (1.16 g, 1.99 mmol), Z-Val-OH (0.712 g, 2.83 mmol) and iPr₂NEt(0.70 mL, 5.42 mmol) in DMF (40 mL) was added HATU (1.10 g, 2.89 mmol)portionwise. The mixture was allowed to stir at room temperature for 1 hand was then poured into ice-water (400 mL) and allowed to stand for 20min. The mixture was filtered and the solid washed with cold water andallowed to air dry overnight to give the Z-protected intermediate. LCMS:Anal. Calcd. for C₄₆H₅₄N₈O₆: 814. found: 815 (M+H)⁺.

The obtained solid was dissolved in MeOH (80 mL), 10% Pd—C (1.0 g) wasadded and the mixture was hydrogenated at room temperature andatmospheric pressure for 3 h. The mixture was then filtered and thefiltrate concentrated in vacuo. The resulting residue was purified byflash chromatography (SiO₂/5-20% MeOH—CH₂Cl₂) to afford the titlecompound (1.05 g, 77%) as a colorless foam. ¹HNMR (400 MHz, DMSO-d₆) δ11.75 (s, 1H), 7.75-7.79 (m, 3H), 7.61-7.67 (m, 5H), 7.49 (s, 1H),7.26-7.28 (m, 1H), 5.05-5.09 (m, 2H), 4.03-4.09 (m, 2H), 3.77-3.80 (m,1H), 3.66-3.70 (m, 1H), 3.52 (s, 3H), 3.40-3.47 (m, 2H), 2.21-2.26 (m,1H), 2.10-2.17 (m, 3H), 1.81-2.02 (m, 6H), 0.77-0.92 (m, 12H).

LCMS: Anal. Calcd. for C₃₈H₄₈N₈O₄: 680. found: 681 (M+H)⁺.

Example cj-15

Preparation of Methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-14)

A mixture of methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-13) (0.329 g, 0.527 mmol) and diphenyl cyanocarbonimidate (0.128 g,0.537 mmol) in iPrOH (10 mL) was stirred at room temperature for 12 h.The resulting solid was filtered and air-dried to give the titlecompound (0.187 g, 43%) as a cream-colored solid. This material was usedas such in the next step without further purification.

LCMS: Anal. Calcd. for C₄₆H₅₂N₁₀O₅: 824. found: 825 (M+H)⁺.

Preparation of methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(cj-15a, R═H)

A solution of methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-14) (0.074 g, 0.090 mmol) and hydrazine hydrate (0.05 mL, 0.88 mmol)in iPrOH (2 mL) was heated at 75° C. for 7 h. The solvent was thenremoved in vacuo and the residue was purified by prep HPLC (Luna 5uC18/MeCN—H₂O—NH₄OAc) to give foam which was lyophilized from CH₃CN—H₂Oto give the title compound (0.032 g, 46%) as a colorless solid.

¹HNMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 11.75 (m, 2H), 10.66-10.84 (m,2H), 7.76-7.79 (m, 3H), 7.62-7.74 (m, 4H), 7.49-7.51 (m, 1H), 7.24-7.29(m, 2H), 5.28-5.32 (m, 1H), 5.05-5.08 (m, 2H), 4.04-4.09 (m, 3H),3.87-3.94 (m, 2H), 3.72-3.81 (m, 2H), 3.53 (s, 3H), 2.09-2.17 (m, 2H),1.90-2.02 (m, 6H), 0.81-0.99 (m, 12H).

LCMS: Anal. Calcd. for C₄₀H₅₀N₁₂O₄: 762. found: 763 (M+H)⁺.

Preparation of Methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-(5-amino-1-methyl-1H-1,2,4-triazol-3-ylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-15b, R=Me)

A solution of methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-14) (0.105 g, 0.128 mmol) and N-methylhydrazine (0.010 mL, 0.188mmol) in iPrOH (2 mL) was heated at 75° C. for 3 h. A second portion ofN-methylhydrazine (0.010 mL, 0.188 mmol) was added and heating wascontinued for 7 h. The volatiles were then removed in vacuo and theresidue was purified by prep HPLC (Luna 5u C18/MeCN—H₂O—NH₄OAc) to givea foam which was further purified by flash chromatography (SiO₂/0-20%MeOH—CH₂Cl₂). The resulting material was lyophilized from CH₃CN—H₂O togive the title compound (0.029 g, 29%) as a colorless solid.

¹HNMR (400 MHz, DMSO-d₆) δ 13.79 (s, 0.4H), 12.19 (s, 1H), 11.76 (m,1.6H), 7.77-7.85 (m, 4H), 7.62-7.71 (m, 4H), 7.49-7.51 (m, 1H),7.24-7.29 (m, 1H), 6.31 (d, J=9.1 Hz, 0.5H), 6.09 (d, J=9.1 Hz, 1.5H),5.87 (s, 1H), 5.34-5.36 (m, 1H), 5.04-5.08 (m, 2H), 4.89 (s, 1H), 4.75(s, 2H), 3.53 (s, 3H), 2.10-2.17 (s, 3H), 1.94-2.02 (m, 6H), 0.81-0.98(m, 12H).

LCMS: Anal. Calcd. for C₄₁H₅₂N₁₂O₄: 776. found: 777 (M+H)⁺.

HRMS: Anal. Calcd. for C₄₁H₅₂N₁₂O₄: 776.4234. found: 777.4305 (M+H)⁺.

Example cj-15c methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1,3-thiazol-2-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example cj-15c was prepared by the condensation of Intermediate cj-13with 2-(methylthio)-4,5-dihydrothiazole (Aldrich) using conditionsanalogous to those in the preparation of Intermediate cj-4. LCMS: Anal.Calcd. for C₄₁H₅₁N₉O₄S: 765. found: 766 (M+H)⁺.

Example 15-d methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-4-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

Example cj-15d was prepared by the condensation of Intermediate cj-13with 4,6-dichloropyrimidine (Aldrich) using conditions analogous tothose in the preparation of Intermediate cj-4, followed by hydrogenationwith 10% Pd—C. LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₄: 758. found: 759(M+H)⁺.

Example cj-16 and cj-17

Preparation of methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(5-amino-1,2,4-oxadiazol-3-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(cj-16)

A solution of methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-14) (0.120 g, 0.205 mmol) and hydroxylamine hydrochloride (0.0213 g,0.307 mmol) in iPrOH (5 mL) was heated at 75° C. for 3 h. A secondportion of hydroxylamine hydrochloride (0.0213 g, 0.307 mmol) was addedand heating continued for 7 h. The volatiles were then removed in vacuoand the residue was purified by prep HPLC (Luna 5u C18/MeCN—H₂O—NH₄OAc)to give a foam which was further purified by flash chromatography(SiO₂/5% MeOH—CH₂Cl₂). The resulting colorless wax was lyophilized fromCH₃CN—H₂O to give the title compound (0.0344 g, 22%) as a colorlesssolid.

¹HNMR (400 MHz, DMSO-d₆) δ 12.18-12.22 (m, 1H), 11.80 (s, 1H), 11.75 (s,1 h), 8.03-8.06 (m, 1H), 7.77 (app d, J=8.1 Hz, 2H), 7.62-7.73 (m, 4H),7.50 (dd, J=2.0, 5.5 Hz, 1H), 7.24-7.29 (m, 2H), 5.69 (s, 1H), 5.06-5.11(m, 2H), 4.14 (t, J=8.6 Hz, 1H), 4.06 (unresolved dd, J=8.0, 8.6 Hz,1H), 3.78-3.90 (m, 3H), 3.53 (s, 3H), 3.01 (br s, 2H), 2.10-2.19 (m,3H), 1.90-2.04 (m, 5H), 0.81-0.96 (m, 12H).

LCMS: Anal. Calcd. for C₄₀H₄₉N₁₁O₅: 763. found: 764 (M+H)⁺.

Preparation of methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(cyano(dimethyl)carbamimidoyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate(cj-17)

A solution of methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(cj-14) (0.115 g, 0.198 mmol) and dimethylamine hydrochloride (0.0257 g,0.315 mmol) in iPrOH (5 mL) was heated at 90° C. for 12 h. A secondportion of dimethylamine hydrochloride (0.0257 g, 0.315 mmol) was addedand heating was continued for 48 h. The volatiles were then removed invacuo and the residue was purified by prep HPLC (Luna 5uC18/MeCN—H₂O—NH₄OAc) and then repurified by flash chromatography(SiO₂/5% MeOH—CH₂Cl₂). The resulting colorless wax was lyophilized fromCH₃CN—H₂O to give the title compound (0.0318 g, 21%) as a colorlesssolid.

¹HNMR (400 MHz, DMSO-d₆) δ 12.22 (m, 0.6H), 11.81 (s, 1H), 11.75 (s,1H), 12.17-12.22 (m, 0.5H), 11.99-12.04 (m, 0.5H), 11.75-11.81 (m, 1H),7.76-7.79 (m, 3H), 7.62-7.73 (m, 5H), 7.50 (t, J=2.0 Hz, 1H), 7.23-7.29(m, 1H), 6.64 (d, J=8.1 Hz, 1H), 5.06-5.08 (m, 2H), 4.47 (t, J=8.1 Hz,2H), 4.06 (unresolved dd, J=8.0, 8.6 Hz, 1H), 3.84-3.90 (m, 2H),3.76-3.82 (m, 3H), 3.53 (s, 3H), 3.00 (s, 6H), 2.11-2.20 (m, 3H),1.90-2.04 (m, 5H), 0.97 (d, J=6.5 Hz, 3H), 0.89-0.91 (m, 6H), 0.84 (d,J=6.5 Hz, 3H).

LCMS: Anal. Calcd. for C₄₂H₅₃N₁₁O₄: 775. found: 776 (M+H)⁺

Example cj-20

Preparation of methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-3-pyridinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate(cj-20)

To a solution of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(cj-13) (0.060 g, 0.103 mmol) in DMF (2 mL) was added iPr₂NEt (0.18 mL,1.02 mmol), (S)-3-methyl-2-(pyridin-3-ylamino)butanoic acid (Cap-88)(0.040 g, 0.206 mmol) and HATU (0.078 g, 0.205 mmol). The reactionmixture was stirred for 1.5 h at room temperature and then it wasdirectly purified by prep HPLC (Luna 5u C18/MeCN—H₂O—NH₄OAc). Theresulting solid was repurified by flash chromatography (SiO₂/0-10%MeOH—CH₂Cl₂) and the obtained product was lyophilized from CH₃CN—H₂O togive the title compound (0.044 g, 56%) as a solid.

¹HNMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 11.76 (s, 1H), 8.07 (d, J=2.6Hz, 1H), 7.62-7.85 (m, 8H), 7.49-7.51 (m, 2H), 7.24-7.29 (m, 1H),6.99-7.06 (m, 2H), 6.46-6.49 (m, 0.5H), 5.97-5.99 (m, 0.5H), 5.71 (d,J=9.0 Hz, 1H), 5.55 (d, J=10.6 Hz, 1H), 5.22-5.44 (m, 1H), 5.03-5.09 (m,2H), 4.04-4.13 (m, 2H), 3.78-3.90 (m, 3H), 3.66-3.71 (m, 1H), 3.53 (s,3H), 2.03-2.19 (m, 2H), 1.84-2.01 (m, 4H), 0.81-1.01 (m, 12H).

LCMS: Anal. Calcd. for C₄₃H₅₁N₉O₄: 757. found: 758 (M+H)⁺.

Similarly, the following examples were prepared according to therepresentative method above;

Example Compound Name Structure LCMS cj-20a (from cj- 22 and Cap-88)methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N-3-pyridinyl-L-valyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₇N₉O₄: 729; found: 730 (M + H)⁺. cj-20b(from cj- 23 and Cap-88) methyl ((1S,2R)-2- methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1- (N-3-pyridinyl-L- valyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₅₁N₉O₅: 773; found: 774 (M + H)⁺. cj-20c(from cj- 24 and Cap-88) N-((1S)-1-(((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2-methylpropyl)-3- pyridinamine

LCMS: Anal. Calcd. for C₄₈H₅₅N₉O₂: 789; found: 790 (M + H)⁺. cj-20d(from cj- 12 and Cap-88) methyl ((1S)-2- methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1- (N-5-pyrimidinyl- L-valyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₄: 758; found: 759 (M + H)⁺.

Preparation of Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(cj-12)

Synthesized from Intermediate-28d and Cap-51 as in Example 28e, followedby Boc removal with TFA/CH₂Cl₂ and free base formation with MCX resin.

¹HNMR (400 MHz, MeOH-d₄) δ 7.79-7.82 (m, 3H), 7.65-7.75 (m, 5H), 7.48(s, 1H), 7.32 (s, 1H), 5.19 (dd, J=5.5, 5.7 Hz, 1H), 4.75 (t, J=7.8 Hz,1H), 4.25 (d, J=7.3 Hz, 1H), 3.88-4.04 (m, 2H), 3.67 (s, 3H), 3.35-3.51(m, 3H), 2.43-2.51 (m, 1H), 2.02-2.38 (m, 7H), 0.97 (d, J=6.5 Hz, 3H),0.92 (d, J=6.9 Hz, 3H).

LCMS: Anal. Calcd. for C₃₃H₃₉N₇O₃: 581. found: 582 (M+H)⁺.

Preparation of Methyl(S)-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)propan-2-ylcarbamate(cj-22)

Synthesized from Intermediate-28d and Cap-52 as in Example 28e, followedby Boc removal with TFA/CH₂Cl₂ and free base formation with MCX resin.

¹HNMR (400 MHz, MeOH-d₄) δ 7.68-7.79 (m, 4H), 7.59-7.65 (m, 4H), 7.44(d, J=6.6 Hz, 1H), 7.37 (s, 0.3H), 7.27 (s, 0.7H), 5.18 (dd, J=4.0, 7.6Hz, 1H), 4.74 (t, J=8.0 Hz, 1H), 4.46 (dd, J=6.8, 13.9 Hz, 1H), 3.84(unresolved dd, J=6.1, 6.5 Hz, 1H), 3.62 (s, 3H), 3.54 (s, 1H),3.32-3.46 (m, 3H), 2.40-2.46 (m, 1H), 2.26-2.39 (m, 2H), 2.14-2.24 (m,2H), 2.01-2.12 (m, 2H), 0.32 (d, J=7.1 Hz, 3H).

LCMS: Anal. Calcd. for C₃₁H₃₅N₇O₃: 553. found: 554 (M+H)⁺.

Preparation of Methyl(2S,3R)-3-methoxy-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(cj-23)

Synthesized from Intermediate-28d and Cap-86 as in Example 28e, followedby Boc removal with TFA/CH₂Cl₂ and free base formation with MCX resin.

¹HNMR (400 MHz, MeOH-d₄) δ 7.72 (m, 4H), 7.64-7.69 (m, 4H), 7.48 (d,J=4.1 Hz, 1H), 7.38 (s, 0.3H), 7.33 (s, 0.7H), 5.51-5.54 (m, 0.2H), 5.22(dd, J=4.9, 7.6 Hz, 0.8H), 4.76 (t, J=8.0 Hz, 1H), 4.48 (d, J=5.1 Hz,0.8H), 4.35-4.36 (m, 0.2H), 3.90-3.99 (m, 1H), 3.68 (s, 3H), 3.54 (s,1H), 3.35-3.48 (m, 4H), 3.29 (s, 3H), 2.42-2.50 (m, 1H), 2.30-2.37 (m,2H), 2.19-2.26 (m, 2H), 2.05-2.15 (m, 2H), 1.19 (d, J=6.1 Hz, 3H).

LCMS: Anal. Calcd. for C₃₃H₃₉N₇O₄: 597. found: 598 (M+H)⁺.

Preparation of(R)-2-(Diethylamino)-2-phenyl-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethanone(cj-24)

Synthesized from Intermediate-28d and Cap-2 as in Example 28e, followedby Boc removal with TFA/CH₂Cl₂ and free base formation with MCX resin.

¹HNMR (400 MHz, MeOH-d₄) δ 7.59-7.82 (m, 10H), 7.36-7.51 (m, 4H),7.01-7.15 (m, 1H), 5.09-5.13 (m, 2H), 4.77 (t, J=8.5 Hz, 1H), 4.03-4.05(m, 1H), 3.67-3.93 (m, 1H), 3.35-3.47 (m, 2H), 3.18-3.23 (m, 1H),2.91-3.07 (m, 2H), 2.70-2.84 (m, 2H), 2.34-2.60 (m, 2H), 1.97-2.24 (m,5H), 1.07-1.17 (m, 6H).

LCMS: Anal. Calcd. for C₃₈H₄₃N₇O: 613. found: 614 (M+H)⁺.

The following were prepared according to the procedure in example 28starting with 28d. The caps are given in the table in the order theywere appended to 28d. Where a cap number is not given the correspondingcarboxylic acid is commercially available.

Ex- am- Compound ple Name Structure LCMS Cap cj- 32 methyl ((1S)-2-((2S)- 2-(5-(4′- (2-((2S)-1- ((2R)- 2- (diethylamino)- 2-phenyl-acetyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)- 2-oxo-1-(1H- 1,2,3-triazol-4-ylmethyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₅H₅₁N₁₁O₄: 809; found: 810 (M + H)⁺.  2/ 128cj- 33 methyl ((1S)- 2-((2S)-2-(5- (4′-(2-((2S)- 1-(N- (methoxy-carbonyl)- L-alanyl)- 2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)- 2-oxo-1-(1H-1,2,3-traizol- 4-ylmethyl) ethyl) carbamate

LCMS: Anal. Calcd. for C₃₈H₄₃N₁₁O₆: 749; found: 750 (M + H)⁺.  52/ 128cj- 34 methyl ((1S)- 1-(((2S)-2-(5- (4′-(2-((2S)- 1-((2S)-2- ((methoxy-carbonyl) amino)-3-(1H- 1,2,3-triazol- 4-yl) propanoyl)-2-pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1-pyrrolidinyl) carbonyl)- 2-methyl- propyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₄₇N₁₁O₆: 777; found: 777 (M + H)⁺.  51/ 128cj- 35 methyl ((1S)- 2-((2S)-2-(5- (4′-(2-((2S)-1- ((2S,3R)-3-methoxy-2- ((methoxy- carbonyl) amino) butanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)-2-oxo-1-(1H- 1,2,3-triazol- 4-ylmethyl) ethyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₄₇N₁₁O₇: 793; found: 794 (M + H)⁺.  86/ 128cj- 36 methyl ((1S)- 2-((2S)-2-(5- (4′-(2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenylacetyl)- 2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)- 2-oxo-1-(1H- pyrazol-1-ylmethyl)- ethyl) carbamate

LCMS: Anal. Calcd. for C₄₆H₅₂N₁₀O₄: 808; found: 809 (M + H)⁺.  2/ 129cj- 37 methyl ((1S)- 2-((2S)-2-(5- (4′-(2-((2S)- 1-(N- (methoxy-carbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(1H-pyrazol-1- ylmethyl) ethyl) carbamate

LCMS: Anal. Calcd. for C39H44N10O6: 748; found: 749 (M + H)⁺.  52/ 129cj- 38 methyl ((1S)- 1-(((2S)-2-(5- (4′-(2-((2S)- 1-((2S)-2- ((methoxy-carbonyl) amino)-3- (1H-pyrazol- 1-yl) propanoyl)- 2- pyrrolidinyl)-1H-imidazol- 5-yl)-4- biphenylyl)- 1H- imidazol-2- yl)-1- pyrroldinyl)carbonyl)- 2-methyl- propyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₄₇N₁₁O₇: 776; found: 777 (M + H)⁺.  51/ 129cj- 39 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy-carbonyl)-O- methyl-L- threonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(1H-pyrazol-1- ylmethyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₈N₁₀O₇: 792; found: 793 (M + H)⁺.  86/ 129cj- 40 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2-(diethylamino)- 2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)- 1-((1-methyl-1H-imidazol- 4-yl)methyl)-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₇H₅₄N₁₀O₄: 822; found: 823 (M + H)⁺.  2/ 127cj- 41 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy-carbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 1-((1-methyl-1H-imidazol- 4-yl)methyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₄₆N₁₀O₆: 762; found: 763 (M + H)⁺.  52/ 127cj- 42 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((2S)- 2-((methoxy-carbonyl) amino)-3-(1- methyl-1H- imidazol-4- yl)propanoyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₆: 790; found: 791 (M + H)⁺.  51/ 127cj- 43 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3-methoxy-2- ((methoxy- carbonyl) amino)butanoyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl)-1- ((1-methyl-1H- imidazol-4- yl)methyl)-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₇: 806; found: 806 (M + H)⁺.  86/ 127cj- 44 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethylamino)- 2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-1-((1-methyl-1H- imidazol-5- yl)methyl)-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₇H₅₄N₁₀O₄ 822; found: 823 (M + H)⁺.  2/ 126 cj-45 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy- carbonyl)-L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 1-((1-methyl- 1H-imidazol-5-yl)methyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₄₆N₁₀O₆: 762; found: 763 (M + H)⁺.  52/ 126cj- 46 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2S)- 2-((methoxy-carbonyl) amino)-3-(1- methyl-1H- imidazol-5- yl)propanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₆ 790; found: 791  51/ 126 cj- 47methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3- methoxy-2-((methoxy- carbonyl) amino)butanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-1-((1-methyl-1H- imidazol-5- yl)methyl)-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₁₀O₇ 806; found: 807 (M + H)⁺.  86/ 126cj- 48 methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1-(((2S)- 4-oxo-2- azetidinyl) carbonyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₃₅H₃₈N₈O₅ 650; found: 651 (M + H)⁺.  52/ — cj-49 methyl (2S)-2- (((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy- carbonyl)-L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-1- azetidine- carboxylate

LCMS: Anal. Calcd. for C₃₇H₄₂N₈O₆ 694; found: 695 (M + H)⁺.  52/ 114 cj-50 methyl (2S)-2- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)- 1-pyrrolidinyl) carbonyl)-1- azetidine-carboxylate

LCMS: Anal. Calcd. for C₄₄H₅₀N₈O₄ 754; found: 755 (M + H)⁺.  2/ 114 cj-51 methyl ((1S)-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- 1-methyl-3- oxopropyl)carbamate

LCMS: Anal. Calcd. for C₄₄H₅₂N₈O₄ 756; found: 757 (M + H)⁺.  2/ 115 cj-52 methyl ((1R)-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- 1-isopropyl-3-oxopropyl) carbamate

LCMS: Anal. Calcd. for C₄₆H₅₆N₈O₄ 784; found: 785 (M + H)⁺.  2/ 116 cj-53 methyl ((1S)-1- benzyl-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-(diethyl- amino)- 2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- 3-oxopropyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₅₆N₈O₄ 833; found: 834 (M + H)⁺.  2/ 96 cj-54 methyl ((1R)-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- 3-oxo-1-(2-thienylmethyl) propyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₄N₈O₄S 838; found: 839 (M + H)⁺.  2/ 119 cj-55 methyl ((1R)-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- 3-oxo-1-(3-thienylmethyl) propyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₄N₈O₄S 838; found: 839 (M + H)⁺.  2/ 120 cj-56 methyl ((1S)-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- 3-oxo-1-(2-thienylmethyl) propyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₄N₈O₄S 838; found: 839 (M + H)⁺.  2/ 118 cj-57 methyl ((1S,3R)- 3-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl-amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) carbonyl)cyclopenytyl) carbamate

LCMS: Anal. Calcd. for C₄₆H₅₄N₈O₄ 782; found: 783 (M + H)⁺.  2/ 99a cj-58 methyl ((1R)-1- benzyl-3-((2S)- 2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethyl- amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)- 3-oxopropyl)carbamate

LCMS: Anal. Calcd. for C₅₀H₅₆N₈O₄ 832; found: 833 (M + H)⁺.  2/ 117 cj-59 methyl ((1R)-3- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- (diethyl-amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 1-(2-fluoro-benzyl)-3- oxopropyl) carbamate

LCMS: Anal. Calcd. for C₅₀H₅₅N₈O₄F 850; found: 851 (M + H)⁺.  2/ 100 cj-60 methyl ((1R,3S)-3- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl-amino)-2- phenylacetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclopentyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₅₄N₈O₄ 782; found: 783 (M + H)⁺.  2/ 99 cj-61 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- (((1R,3S)-3- ((methoxy-carbonyl) amino) cyclopentyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methyl- propyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₅₀N₈O₆ 750; found: 751 (M + H)⁺.  52/ 99a cj-62 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- (((1S,3R)-3- ((methoxy-carbonyl) amino) cyclopentyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₅₀N₈O₆ 750; found: 751 (M + H)⁺.  52/ 99 cj-63 methyl ((1R)-2- ((2S)-2-(5-(4′- (2-((2S)-1- (((1R,3S)-3- ((methoxy-carbonyl) amino) cyclopentyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₄₈N₈O₆ 748; found: 785 (M + H)⁺.  4/ 99a cj-64 methyl ((1R)-2- ((2S)-2-(5-(4′- (2-((2S)-1- (((1S,3R)-3- ((methoxy-carbonyl) amino) cyclopentyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₄₈N₈O₆ 748; found: 785 (M + H)⁺.  4/ 99 cj-65 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-2- ((methoxy-carbonyl) amino)-3-(2- pyridinyl) propanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₄₉N₉O₆ 787; found: 788 (M + H)⁺.  51/ 93 cj-66 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy- carbonyl)-L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1- (2- pyridinyl- methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₅N₉O₆ 759; found: 760 (M + H)⁺.  52/ 93 cj-67 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3- methoxy-2-((methoxy- carbonyl) amino) butanonyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(2-pyridinyl- methyl) ethyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₄₉N₉O₇ 803; found: 804 (M + H)⁺.  86/ 93 cj-68 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-(diethyl-amino)-2- phenylacetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2- oxo-1-(2- pyridinyl-methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₃N₉O₄ 819; found: 820 (M + H)⁺.  2/ 93 cj-69 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((cis- 4-((methoxy-carbonyl) amino) cyclohexyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methyl- propyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₂N₈O₆ 764; found: 765 (M + H)⁺.  51/ 104 cj-70 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((trans- 4-((methoxy-carbonyl) amino) cyclohexyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methyl- propyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₂N₈O₆ 764; found: 765 (M + H)⁺.  51/ 105 cj-71 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((cis-4- (diethylamino)cyclohexyl) carbonyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₅₈N₈O₄ 762; found: 763 (M + H)⁺.  51/ 106 cj-72 methyl ((1S,2R)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((cis-4- (diethyl-amino) cyclohexyl) carbonyl)- 2-pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) carbonyl)-2- methoxy-propyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₅₈N₈O₅ 778; found: 779 (M + H)⁺.  86/ 106 cj-73 cis-4-(((2S)- 2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethyl- amino)-2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-N,N- diethyl- cyclo-hexanamine

LCMS: Anal. Calcd. for C₄₉H₆₂N₈O₂ 794; found: 795 (M + H)⁺.  2/ 106 cj-74 methyl ((1S)- 2-((2S)-2-(5-(4′- (2-((2S)-1- ((cis-4- (diethyl- amino)cyclohexyl) carbonyl)- 2-pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 1-methyl-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C₄₂H₅₄N₈O₄ 734; found: 735 (M + H)⁺.  52/ 106 cj-75 methyl ((1S)-1- ((1-benzyl- 1H-imidazol-4- yl)methyl)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3- methoxy- 2-((methoxy- carbonyl)amino) butanoyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)- 2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₄N₁₀O₇ 882; found: 883 (M + H)⁺.  86/ 108cj- 76 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2S)- 3-(1-benzyl-1H-imidazol-4- yl)-2- ((methoxy- carbonyl) amino) propanoyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₄N₁₀O₆ 866; found: 867 (M + H)⁺.  51/ 108cj- 77 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-3-(1-benzyl-1H- imidazol-4- yl)-2- ((methoxy- carbonyl) amino) propanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₆H₅₀N₁₀O₆ 838; found: 839 (M + H)⁺.  52/ 108cj- 78 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3-methoxy-2- ((methoxy- carbonyl) amino) butanoyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl)-2- oxo-1-(1,3- thiazol-4- ylmethyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₇N₉O₇S 809; found: 810 (M + H)⁺.  86/ 107cj- 79 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-2-((methoxy-carbonyl) amino)-3-(1,3- thiazol-4- yl)propanoyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₇N₉O₆S 793; found: 794 (M + H)⁺.  51/ 107cj- 80 methyl ((1S)-2- ((2)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(1,3-thiazol-4- ylmethyl) ethyl) carbamate

LCMS: Anal. Calcd. for C₄₆H₅₁N₉O₄S 825; found: 826 (M + H)⁺.  2/ 107 cj-81 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy- carbonyl)-L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(1,3- thiazol-4- ylmethyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₃₉H₄₃N₉O₆S 765; found: 766 (M + H)⁺.  51/ 107cj- 82 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3-methoxy-2- ((methoxy- carbonyl) amino) butanoyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl)-2- oxo-1-(3- pyridinyl- methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₄₉N₉O₇ 803; found: 804 (M + H)⁺.  86/ 109 cj-83 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-2- ((methoxy-carbonyl) amino)-3- methyl- butanoyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(3-pyridinyl- methyl) ethyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₄₉N₉O₆ 787; found: 788 (M + H)⁺.  51/ 109 cj-84 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(3-pyridinyl- methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₃N₉O₄ 819; found: 820 (M + H)⁺.  2/ 109 cj-85 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-N- (methoxy- carbonyl)-L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(3- pyridinyl-methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₅N₉O₆ 759; found: 760 (M + H)⁺.  52/ 109 cj-86 methyl ((1R,3S)-3- (((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-3- methoxy-2-((methoxy- carbonyl) amino) butanoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- carbonyl)cyclopentyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₀N₈O₇ 766; found: 767 (M + H)⁺.  86/ 99 cj-87 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S,3R)-3- methoxy-2-((methoxy- carbonyl) amino) butanoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(4-pyridinyl- methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₄₉N₉O₇ 803; found: 804 (M + H)⁺.  86/ 110 cj-88 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-2- ((methoxy-carbonyl) amino)-3- methyl- butanoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(4-pyridinyl- methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₃H₄₉N₉O₆ 787; found: 788 (M + H)⁺.  51/ 110 cj-89 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(4- pyridinyl-methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₃N₉O₄ 819; found: 820 (M + H)⁺.  2/ 110 cj-90 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy- carbonyl)-L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-(4- pyridinyl-methyl)ethyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₄₅N₉O₆ 759; found: 760 (M + H)⁺.  52/ 110 cj-91 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- (O-hydroxy- (methoxy)phosphoryl)-N- (methoxy- carbonyl)- L-tyrosyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₅H₅₃N₈O₁₀ P 896; found: 897 (M + H)⁺.  51/ 111cj- 92 methyl ((1S,2R)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(O-hydroxy(methoxy) phosphoryl)-N- (methoxy-carbonyl)- L-tyrosyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2- methoxy-propyl) carbamate

LCMS:Anal. Calcd. for C₄₅H₅₃N₈O₁₁ P 912; found: 913 (M + H)⁺.  86/ 111cj- 93 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- (((1S,2R)-2-((methoxy- carbonyl) amino) cyclohexyl) carbonyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)-2- methyl- propyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₅₂N₈O₆ 764; found: 765 (M + H)⁺.  98/ 51 cj-94 methyl ((1R,2S)-2- (((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclohexyl)carbamate

LCMS: Anal. Calcd. for C₄₇H₅₆N₈O₄ 796; found: 797 (M + H)⁺.  98/ 2 cj-95 methyl ((1R)-2- ((2S)-2-(5-(4′- (2-((2S)-1- (((1S,2R)-2- ((methoxy-carbonyl) amino) cyclohexyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate

LCMS: Anal. Calcd. for C₄₅H₅₀N₈O₆ 798; found: 799 (M + H)⁺.  98/ 4 cj-96 methyl ((1R,2S)-2- (((2S)-2-(5-(4′- (2-((2S)-1-N- (methoxy-carbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclohexyl)carbamate

LCMS: Anal. Calcd. for C₄₀H₄₈N₈O₆ 736; found: 737 (M + H)⁺.  98/ 51 cj-97 methyl ((1R,2S)-2- (((2S)-2-(5-(4′- (2-((2S)-1- ((cis-4- (diethyl-amino) cyclohexyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclohexyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₆₀N₈O₄ 788; found: 789 (M + H)⁺.  98/ 106 cj-98 methyl ((1R,2S)-2- (((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- acetamido-2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclohexyl) carbamate

LCMS: Anal. Calcd. for C₄₅H₅₀N₈O₅ 782; found: 783 (M + H)⁺.  98/ 130 cj-99 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-3-(1H-indol-3-yl)-2- ((methoxy- carbonyl) amino) propanoyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl) carbamate

LCMS: Anal. Calcd. for C₅₆H₅₁N₉O₆ 825; found: 826 (M + H)⁺.  51/ 112 cj-100 methyl ((1S)-1-(1H- indol-3-ylmethyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3- methoxyl-2- ((methoxy-carbonyl) amino)butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

LCMS:Anal. Calcd. for C₄₆H₅₁N₉O₇ 841; found: 842 (M + H)⁺.  86/ 112 cj-101 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 1-(1H-indol-3-ylmethyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₅₁H₅₅N₉O₄ 857; found: 858 (M + H)⁺.  2/ 112 cj-102 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3- (1H-indol-3-yl)-2- ((methoxy- carbonyl) amino) propanoyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₄₇N₉O₆ 797; found: 798 (M + H)⁺.  52/ 112 cj-103 methyl ((1S)-1- (4-(amino- methyl) benzyl)-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2S)- 2-((methoxy- carbonyl) amino)-3- methyl) butanoyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₅H₅₃N₉O₆ 815; found: 816 (M + H)⁺. see text cj-104 methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-(O- benzyl-N- (methoxy-carbonyl)- L-tyrosyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)- 2-methyl-propyl) carbamate

LCMS: Anal. Calcd. for C₅₁H₅₆N₈O₇ 892; found: 893 (M + H)⁺.  51/ 113 cj-105 methyl ((1S,2R)-1- (((2S)-2-(5-(4′- (2-((2S)-1-(O- benzyl-N-(methoxy- carbonyl)- L-tyrosyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methoxypropyl) carbamate

LCMS: Anal. Calcd. for C₅₁H₅₆N₈O₈ 908; found: 909 (M + H)⁺.  86/ 113 cj-106 methyl ((1S)-1- (4-(benzyloxy) benzyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethyl- amino)-2- phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₅₆H₆₀N₈O₅ 924; found: 925 (M + H)⁺.  2/ 113 cj-107 methyl ((1S)-1- (4-(benzyloxy) benzyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1- (N- (methoxy- carbonyl)- L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₉H₅₂N₈O₇ 864; found: 865 (M + H)⁺.  52/ 113 cj-108 methyl ((1R,2R)-2- (((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxy-carbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclopentyl)carbamate

LCMS: Anal. Calcd. for C₃₉H₄₆N₈O₆ 722; found: 723 (M + H)⁺. 122/ 52 cj-109 methyl ((1R,2R)-2- (((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclopentyl)carbamate

LCMS: Anal. Calcd. for C₄₆H₅₄N₈O₄ 782; found: 783 (M + H)⁺. 122/ 2 cj-110 methyl ((1R)-2- ((2S)-2-(5-(4′- (2-((2S)-1- (((1R,2R)-2- ((methoxy-carbonyl) amino) cyclopentyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₄₈N₈O₆ 784; found: 785 (M + H)⁺. 122/ 4 cj-111 methyl ((1S)-1- (4-hydroxy- benzyl)-2- ((2S)-2-(5-(4′- (2-((2S)-1-((2S)-2- ((methoxy- carbonyl) amino)-3- methyl- butanoyl)-2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₅₀N₈O₇ 802; found: 803 (M + H)⁺. see text cj-112 methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (diethyl-amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 1-(4-hydroxy-benzyl)-2- oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₉H₅₄N₈O₅ 834; found: 835 (M + H)⁺. see text cj-113 methyl ((1S)-1- (4-hydroxy- benzyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxy- carbonyl)- L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₂H₄₆N₈O₇ 774; found: 775 (M + H)⁺. see text cj-114 methyl ((1S)-1- (4-(acetamido- methyl)benyzl)- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2S)-2- ((methoxy- carbonyl) amino)-3- methyl-butanoyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₇H₅₅N₉O₇ 857; found: 585 (M + H)⁺. see text cj-115 methyl ((1S)-1- (4-(((ethyl- carbamoyl) amino) methyl) benzyl)-2-((2S)-2-(5-(4′- (2-((2S)-1- ((2S)-2- ((methoxy- carbonyl) amino)-3-methyl- butanoyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxoethyl) carbamate

LCMS: Anal. Calcd. for C₄₈H₅₈N₁₀O₇ 886; found: 887 (M + H)⁺. see textcj- 116 methyl ((1S,2S)- 2-(((2S)-2- (5-(4′-(2- ((2S)-1-((2R)-2-(diethyl- amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)cyclopentyl) carbamate

LCMS: Anal. Calcd. for C₄₆H₅₄N₈O₄ 782; found: 783 (M + H)⁺. 121/ 2 cj-117 methyl ((1R)-2- ((2S)-2-(5-(4′- (2-((2S)-1- (((1S,2S)- 2-((methoxy-carbonyl) amino) cyclopentyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate

LCMS: Anal. Calcd. for C₄₄H₄₈N₈O₆ 784; found: 785 (M + H)⁺. 121/ 4 cj-118 methyl ((1S,2S)- 2-(((2S)-2-(5- (4′-(2-((2S)- 1-(N- (methoxy-carbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) cyclopentyl)carbamate

LCMS: Anal. Calcd. for C₃₉H₄₆N₈O₆ 722; found: 723 (M + H)⁺. 121/ 52 cj-119 methyl ((1S)-1- (((2S)-2-(5- (4′-(2-((2S)- 1-(N- (methoxy-carbonyl)- O-methyl- L-homoseryl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)-2-methylpropyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₅₀N₈O₇ 754; found: 755 (M + H)⁺.  51/ 87 cj-120 methyl ((1S)-3- methoxy-1- (((2S)-2-(5- (4′-(2-((2S)- 1-(N-(methoxy- carbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl) propyl)carbamate

LCMS: Anal. Calcd. for C₃₈H₄₆N₈O₇ 726; found: 727 (M + H)⁺.  52/ 87 cj-121 methyl ((1S,2R)- 2-methoxy-1- (((2S)-2-(5- (4′-(2-((2S)- 1-(N-(methoxy- carbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl) propyl) carbamate

LCMS: Anal. Calcd. for C₄₀H₅₀N₈O₈ 770; found: 771 (M + H)⁺.  86/ 87 cj-122 methyl ((1S,2S)- 2-(((2S)-2-(5- (4′-(2-((2S)- 1-(N- (methoxy-carbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl) carbonyl)cyclopentyl) carbamate

LCMS: Anal. Calcd. for C₄₁H₅₀N₈O₇ 766; found: 767 (M + H)⁺. 121/ 87

Examples cj-111 to cj-113

For Examples cj-111 to cj-113 the compounds of Examples cj-105 to cj-107were hydrogenated under conditions analogous to those used in Example28, step d (with the exception that K₂CO₃ was not employed).

Preparation of examples cj-103, cj-114 and cj-115

Intermediate cj-124 was prepared by coupling of intermediate cj-12 andCap-122, as described in Example 28, step e. LCMS: Anal. Calcd. forC₆₀H₆₃N₉O₈ 1037. found: 520 (½M+H)⁺. This corresponds to the doublycharged molecular ion.

Example cj-103

Intermediate cj-124 (83.0 mg, 0.08 mmol) was dissolved in DMF (5 mL) andpiperidine (1 mL) was added at room temperature. After 2 h the volatileswere removed in vacuo and the residue was purified by preparative HPLC(YMC-Pack C-18, 30×100 mm, CH₃CN—H₂O-TFA) to give the TFA salt of theamine (87.0 mg, 94%). LCMS: Anal. Calcd. for C₄₅H₅₃N₉O₆ 815. found: 816(M+H)⁺.

Examples cj-114 to cj-115

The product from Example cj-103 was acylated with either aceticanhydride or ethyl isocyanate as shown in scheme under conditionsanalogous to those in Example 25.

Example cj-114, LCMS: Anal. Calcd. for C₄₇H₅₅N₉O₇ 857. found: 858(M+H)⁺.

Example cj-115, LCMS: Anal. Calcd. for C₄₈H₅₈N₁₀O₇ 886. found: 887(M+H)⁺.

The following examples were prepared from intermediate 1e using aprocedure analogous to Example 1. The appended cap is indicated in theTable and where no cap number is give the carboxylic acid wascommercially available.

Example Compound Name Structure Cap LCMS cj-125 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1H-1,2,3-triazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-1,2,3-triazol-4- ylmeth yl)ethyl)- carbamate

128 LCMS: Anal. Calcd. for C₄₀H₄₄N₁₄O₆: 816; found: 817 (M + H)⁺. cj-126dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2S)- 4-oxo-4,2- butanediyl)))- biscarbamate

115 LCMS: Anal. Calcd. for C₃₈H₄₆N₈O₆ 710; found: 711 (M + H)⁺. cj-127dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((3R)- 4-methyl-1-oxo- 1,3- pentanediyl)))- biscarbamate

116 LCMS: Anal. Calcd. for C₄₂H₅₄N₈O₆ 766; found: 777 (M + H)⁺. cj-128methyl ((1R)-3- ((2S)-2-(5-(4′-(2- (1-((3R)-3- ((methoxycarbonyl)amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1- phenylpropyl)-carbamate

 92 LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₆ 834; found: 835 (M + H)⁺. cj-129methyl ((1S)-3- ((2S)-2-(5-(4′-(2- (1-((3S)-3- ((methoxycarbonyl)amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1- phenylpropyl)-carbamate

 91 LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₆ 834; found: 835 (M + H)⁺. cj-130methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl)amino)-3-(2- pyridinyl)propanoyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(2-pyridinylmethyl)- ethyl)carbamate

 93 LCMS: Anal. Calcd. for C₄₆H₄₈N₁₀O₆ 836; found: 837 (M + H)⁺. cj-131methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3- (1H-imidazol-4-yl)-2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-(1H-imidazol-4- ylmethyl)-2- oxoethyl)carbamate

 94 LCMS: Anal. Calcd. for C₄₂H₄₆N₁₂O₆ 814; found: 815 (M + H)⁺. cj-132(6S,6′S)-6,6′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl)didihydro- 2,4(1H,3H)- pyrimidinedione

— LCMS: Anal. Calcd. for C₃₆H₃₆N₁₀O₆ 704; found: 705 (M + H)⁺. cj-133(4S,5R,4′S,5′R)- 4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl- carbonyl))bis(5-methyl- 1,3-oxazolidin-2-one)

124 LCMS: Anal. Calcd. for C₃₇H₄₀N₈O₅ 676; found: 677 (M + H)⁺. cj-134N-(3-((2S)-2-(5-(4′- (2-((2S)-1-(3- acetamidopropanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-3- oxopropyl)acetamide

— LCMS: Anal. Calcd. for C₃₆H₄₂N₈O₄ 650; found: 651 (M + H)⁺. cj-135dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((3R)- 1-oxo-5-phenyl- 1,3- pentanediyl)))- biscarbamate

 95 LCMS: Anal. Calcd. for C₅₂H₅₈N₈O₆ 890; found: 890 (M + H)⁺. cj-136dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2R)- 4-oxo-1-(2- thienyl)-4,2- butanediyl)))-biscarbamate

119 LCMS: Anal. Calcd. for C₄₆H₅₀N₈O₆S₂ 874; found: 875 (M + H)⁺. cj-137dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2R)- -4-oxo-1-(3- thienyl)-4,2- butanediyl)))-biscarbamate

120 LCMS: Anal. Calcd. for C₄₆H₅₀N₈O₆S₂ 874; found: 875 (M + H)⁺. cj-138dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2S)- -4-oxo-1-(2- thienyl)-4,2- butanediyl)))-biscarbamate

118 LCMS: Anal. Calcd. for C₄₆H₅₀N₈O₆S₂ 874; found: 875 (M + H)⁺. cj-139dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl(1R,2R)-2,1- cyclohexanediyl)bis- carbamate

 97 LCMS: Anal. Calcd. for C₄₄H₅₄N₈O₆ 790; found: 791 (M + H)⁺. cj-140di-tert-butyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2S)-4- (dimethylamino)-1- oxo-1,2- butanediyl)))-biscarbamate

125 LCMS: Anal. Calcd. for C₄₈H₆₈N₁₀O₆ 880; found: 881 (M + H)⁺. cj-141dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl(1R,2S)-2,1- cyclohexanediyl))bis- carbamate

 98 LCMS: Anal. Calcd. for C₄₄H₅₄N₈O₆ 790; found: 791 (M + H)⁺. cj-142(3S,3′S)-4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl))bis (N~1~,n~1~- dimethyl-4-oxo- 1,3-butanediamine

see text LCMS: Anal. Calcd. for C₃₈H₅₂N₁₀O₂ 680; found: 681 (M + H)⁺.cj-143 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2R)- 4-oxo-1-phenyl- 4,2- butanediyl)))- biscarbamate

117 LCMS: Anal. Calcd. for C₅₀H₅₄N₈O₆ 862; found: 863 (M + H)⁺. cj-144dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl(1R,3S)-3,1- cyclopentanediyl))bis- carbamate

 99 LCMS: Anal. Calcd. for C₄₂H₅₀N₈O₆ 762; found: 763 (M + H)⁺. cj-145methyl ((1R)-1- benzyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2-((methoxycarbonyl) amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxoethyl)carbamate

101 LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₆ 834; found: 835 (M + H)⁺. cj-146dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl((2S)-4- (dimethylamino)-1- oxo-1,2- butanediyl)))-biscarbamate

see text LCMS: Anal. Calcd. for C₄₂H₅₆N₁₀O₆ 796; found: 797 (M + H)⁺.cj-147 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis (N,N-dimethyl-1- oxo-3-phenyl-2-propanamine)

 90 LCMS: Anal. Calcd. for C₄₈H₅₄N₈O₂ 774; found: 775 (M + H)⁺. cj-148methyl ((1S)-1- benzyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2S)-2-((methoxycarbonyl) amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxoethyl)carbamate

102 LCMS: Anal. Calcd. for C₄₈H₅₀N₈O₆ 834; found: 835 (M + H)⁺. cj-149dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl(1R,3S)-3,1- cyclopentanediyl))bis- carbamate

 99a LCMS: Anal. Calcd. for C₄₂H₅₀N₈O₆ 806; found: 807 (M + H)⁺. cj-150dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonylcis-4,1- cylcohexanediyl))bis- carbamate

104 LCMS: Anal. Calcd. for C₄₄H₅₄N₈O₆ 790; found: 791 (M + H)⁺. cj-151dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyltrans-4,1- cyclohexanediyl))bis- carbamate

105 LCMS: Anal. Calcd. for C₄₄H₅₄N₈O₆ 790; found: 791 (M + H)⁺. cj-152({cis)-4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl))bis(N,N- diethylcyclo- hexanamine)

106 LCMS: Anal. Calcd. for C₄₈H₆₆N₈O₂ 766; found: 777 (M + H)⁺. cj-153methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl)amino)-3-(1,3- thiazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-(1,3-thiazol- 4- ylmethyl)ethyl)- carbamate

107 LCMS: Anal. Calcd. for C₄₂H₄₄N₁₀O₆ S₂ 848; found: 849 (M + H)⁺.cj-154 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3-(1- benzyl-1H-imidazol-4-yl)-2- ((methoxycarbonyl) amino)propanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-((1- benzyl-1H- imidazol-4- yl)methyl)-2-oxoethyl)carbamate

108 LCMS: Anal. Calcd. for C₅₆H₅₈N₁₂O₆ 994; found: 995 (M + H)⁺. cj-155dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1-pyrrolidinediyl- carbonyl(1S,2S)-2,1- cyclopentanediyl))bis- carbamate

121 LCMS: Anal. Calcd. for C₄₂H₅₀N₈O₆ 762; found: 763 (M + H)⁺. cj-156methyl ((1S)-3- methoxy-1-(((2S)- 2-(5-(4′-(2-((2S)-1- (N-(methoxycarbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- propyl)carbamate

 87 LCMS: Anal. Calcd. for C₄₀H₅₀N₈O₈ 770; found: 771 (M + H)⁺.

Example cj-142

Example cj-142 was prepared from the product obtained in Example cj-140by treatment with 40% TFA in CH₂Cl₂. The mixture was allowed to stir for3 h at room temperature and then concentrated in vacuo. The residue waspurified by prep HPLC (YMC-Pack, C18 30×100 mm, CH₃CN—H₂O-TFA).

Example cj-156

The compound of Example-cj-156 was prepared by carbamoylation of thecompound prepared in Example-cj-142 according to the method shown forCap-51.

Section JG

Method A: LCMS—Xterra MS C-18 3.0×50 mm, 0 to 100% B over 30.0 minutegradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Method B: HPLC—X-Terra C-18 4.6×50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90%methanol 10% water 0.1% TFA

Method C: HPLC—YMC C-18 4.6×50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.2% H₃PO₄, B=90%methanol 10% water 0.2% H₃PO₄.

Method D: HPLC—Phenomenex C-18 4.6×150 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=10% methanol 90% water 0.2% H₃PO₄, B=90%methanol 10% water 0.2% H₃PO₄

Method E: LCMS—Gemini C-18 4.6×50 mm, 0 to 100% B over 10.0 minutegradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Method F: LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minutegradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Method G: HPLC—Phenomenex Gemini C-18 4.6×150 mm, 10 to 80% B over 35minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate

Method H: HPLC—Phenomenex Gemini C-18 4.6×150 mm, 10 to 80% B over 25minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate

Method I: HPLC—Waters-X-Bridge C-18 4.6×150 mm, 10 to 70% B over 30minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mmammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate

Step a:

(3S,3′S,5S,5′S)-tert-butyl5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-1-carboxylate)(1.40 g, 2.13 mmol) was added as a solid to a solution ofbis(2-methoxyethyl)aminosulfur trifluoride (0.87 mL, 4.69 mmol) in 14.0mL CH₂Cl₂ cooled to −78° C. Reaction was stirred at −78° C. for twohours and then warmed to room temperature and stirred for 2 hours.Reaction was poured into saturated sodium bicarbonate solution andstirred until bubbling ceased. Layers were separated and aqueous layerwashed one time with CH₂Cl₂. Combined organics were washed with brine,dried (MgSO₄), filtered, and concentrated to give a yellow oil. The oilwas triturated with CH₂Cl₂ and pentane to yield(3R,3′R,5S,5′S)-tert-butyl5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-fluoropyrrolidine-1-carboxylate)JG-1 as a tan solid (0.98 g, 71%).

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (2H, m) 7.60-7.82 (8H, m) 7.35(2H, m) 5.45 (1H, s) 5.35 (1H, s) 4.85-4.90 (2H, m) 3.69-3.79 (4H, m)2.53-2.61 (2H, m) 2.28-2.37 (2H, m) 1.40 (8H, s) 1.12 (10H, s)

LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10%water 0.1% TFA, (t_(R)=3.04 min) Anal Calcd. for C₃₆H₄₂F₂N₆O₄ 660.70.found 661.68 (M+H)⁺

Step b:

To a solution of (3R,3′R,5S,5′S)-tert-butyl5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-1-carboxylate)(0.098 g, 1.48 mmol) in 4 mL dioxane was added 2.0 mL of a 4.0M solutionof HCl in dioxane. The reaction was stirred for 2 hours at roomtemperature and concentrated under reduced pressure. The resulting tansolid was dried under vacuum to give4,4′-bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyltetrahydrochloride JG-2 (0.89 g, 100% yield). No further purification.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.05 (2H, s), 8.18 (2H, s), 8.00-8.09(4H, m) 7.89 (4H, d, J=7.63 Hz) 5.71 (1H, s) 5.61 (1H, s) 5.24-5.33 (2H,m) 3.92 (2H, d, J=10.68 Hz) 3.63-3.71 (2H, m) 2.79-2.89 (2H, m)

LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10%water 0.1% TFA, (t_(R)=2.12 min) Anal Calcd. for C₂₆H₂₆F₂N₆ 460.53.found 461.37 (M+H)⁺

Step c:

To a stirred solution of4,4′-bis(2-((2S,4R)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyltetrahydrochloride(0.060 g, 0.10 mmol), (S)-2-(methoxycarbonylamino)propanoic acid (0.031g, 0.21 mmol), and HATU (0.081 g, 0.21 mmol) in 3 mL DMF was addeddiisopropylethyl amine (0.11 mL, 0.61 mmol). The reaction was stirred atroom temperature overnight (16 hours) and concentrated under reducedpressure. The crude product was purified by reverse-phase preparativeHPLC and secondly by passing it through a Waters MCX extractioncartridge to provide Dimethyl(2S,2′S)-1,1′-((3R,3′R,5S,5′S)-5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(1-oxopropane-2,1-diyl)dicarbamateJG-3, free base (0.0097 g, 7.5%).

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.91 (2H, m), 7.76-7.84 (3H, m),7.64-7.84 (5H, m), 7.48-7.58 (2H, m), 5.55 (1H, s), 5.11 (1H, s),4.29-4.38 (2H, m), 4.13 (2H, d, J=12.51 Hz), 3.89-3.98 (2H, m), 3.53(6H, s), 2.54-2.64 4H, m), 1.21 (6H, s)

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, (t_(R)=20.40 min)

Nominal/LRMS—Calcd. for C₃₆H₄₀F₂N₈O₆ 718.30. found 719.24 (M+H)⁺

Accurate/HRMS—Calcd. for C₃₆H₄₁F₂N₈O₆ 719.3117. found 719.3114 (M+H)⁺

Structure Compound Name Data

methyl ((1S)-2-((2S,4R)- 4-fluoro-2-(5-(4′-(2- ((2S,4R)-4-fluoro-1-(N-(methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate RT = 13.60 min, method I LRMS: Anal. Calcd. forC₃₆H₄₀F₂N₈O₆ 718.30 found: 719.24 (M + H)⁺ HRMS: Anal. Calcd. forC₃₆H₄₁F₂N₈O₆ 719.3117 found 719.3114 (M + H)⁺

methyl ((1S)-2-((2S,4R)- 4-hydroxy-2-(5-(4′-(2- ((2S,4R)-4-hydroxy-1-(N-(methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate RT = 9.27 min, method H LRMS: Anal. Calcd. forC₃₆H₄₂N₈O₈ 714.77 found: 715.33 (M + H)⁺ HRMS: Anal. Calcd. forC₃₆H₄₃N₈o₈ 715.3204 found: 715.3186 (M + H)⁺

methyl ((1S)-1-(((2S,4R)- 4-hydroxy-2-(5-(4′-(2- ((2S,4R)-4-hydroxy-1-((2S)-2-((methoxy- carbonyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate RT = 15.08 min, methodG LRMS: Anal. Calcd. for C₄₀H₅₀N₈O₈ 770.88 found: 771.76 (M + H)⁺ HRMS:Anal. Calcd. for C₄₀H₅₁N₈O₈ 771.3830 found: 771.3798 (M + H)⁺

dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl((2S,4R)-4-hydroxy- 2,1-pyrrolidinediyl)((1S)-1-cyclopropyl-2-oxo-2,1- ethane- diyl)))biscarbamate RT = 13.67 min,method G LRMS: Anal. Calcd. for C₄₀H₄₆N₈O₈ 766.85 found: 767.65 (M + H)⁺HRMS: Anal. Calcd. for C₄₀H₄₇N₈O₈ 767.3517 found: 767.3483 (M + H)⁺

(3S,5S,3′S,5′S)-5,5′-(4,4′- biphenyldiylbis(1H- imida-zole-5,2-diyl))-bis(1-((2R)-2-(diethyl- amino)-2-phenylacetyl)- 3-pyrrolidinol) RT =15.88 min, method H LRMS: Anal. Calcd. for C₅₀H₅₈N₈O₄ 834.45 found:835.38 (M + H)⁺ HRMS: Anal. Calcd. for C₅₀H₅₉N₈O₄ 835.4659 found:835.4627 (M + H)⁺

methyl ((1S)-2-((2S,4S)- 4-hydroxy-2-(5-(4′-(2- ((2S,4S)-4-hydroxy-1-(N-(methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate RT = 9.99 min, method H LRMS: Anal. Calcd. forC₃₆H₄₂N₈O₈ 714.77 found: 715.71 (M + H)⁺ HRMS: Anal. Calcd. forC₃₆H₄₃N₈O₈ 715.3204 found: 715.3188 (M + H)⁺

methyl ((1S)-1-(((2S,4S)- 4-hydroxy-2-(5-(4′-(2- ((2S,4S)-4-hydroxy-1-((2S)-2- ((methoxycarbonyl)- amino)-3-methyl- butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate RT = 14.12 min, methodH LRMS: Anal. Calcd. for C₄₀H₅₀N₈O₈ 770.88 found: 771.74 (M + H)⁺ HRMS:Anal. Calcd. for C₄₀H₅₁N₈O₈ 771.3830 found: 771.3799 (M + H)⁺

methyl ((1S)-1-(((2S,4S)- 4-fluoro-2-(5-(4′-(2- ((2S,4S)-4-fluoro-1-((2S)-2- ((methoxycarbonyl)- amino)-3-methyl- butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate RT = 17.66 min, methodI LRMS: Anal. Calcd. for C₄₀H₄₈F₂N₈O₆ 774.86 found: 775.49 (M + H)⁺HRMS: Anal. Calcd. for C₄₀H₄₉F₂N₈O₆ 775.3743 found: 775.3717 (M + H)⁺

methyl ((1S)-1-(((2S,4R)- 4-fluoro-2-(5-(4′-(2- ((2S,4R)-4-fluoro-1-((2S)-2- ((methoxycarbonyl)- amino)-4- methylpentanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-3- methylbutyl)carbamate RT = 9.69 min, method ILRMS: Anal. Calcd. for C₄₂H₅₂F₂N₈O₆ 802.92 found: 803.42 (M + H)⁺ HRMS:Anal. Calcd. for C₄₂H₅₃F₂N₈O₆ 803.4056 found: 803.4018 (M + H)⁺

methyl ((1S)-2-((2S,4S)- 4-fluoro-2-(5-(4′-(2- ((2S,4S)-4-fluoro-1-(N-(methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate RT = 13.60 min, method I LRMS: Anal. Calcd. forC₃₆H₄₀F₂N₈O₆ 718.30 found: 719.45 (M + H)⁺ HRMS: Anal. Calcd. forC₃₆H₄₁F₂N₈O₆ 719.3117 found: 719.3090 (M + H)⁺

methyl ((1S)-2-((2S,4S)- 2-(5-(4′-(2-((2S,4S)-1- ((2R)-2-(di-ethylamino)-2- phenylacetyl)-4-fluoro-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-4-fluoro-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate RT = 15.13 min, method ILCMS: Anal. Calcd. for C₄₃H₄₈F₂N₈O₄ 778.91 found: 779.79 (M + H)⁺

methyl ((1S)-1-(((2S,4S)- 2-(5-(4′-(2-((2S,4S)-1- ((2R)-2-(di-ethylamino)-2- phenylacetyl)-4-fluoro-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-4-fluoro-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate RT = 17.51 min, methodI LCMS: Anal. Calcd. for C₄₅H₅₂F₂N₈O₄ 806.96 found: 807.50 (M + H)⁺

methyl ((1S)-1-(((2S,4R)- 4-fluoro-2-(5-(4′-(2- ((2S,4R)-4-fluoro-1-((2S)-2- ((methoxycarbonyl)- amino)-3-methyl- butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate RT = 16.51 min, methodI LRMS: Anal. Calcd. for C₄₀H₄₈F₂N₈O₆ 774.86 found: 775.39 (M + H)⁺HRMS: Anal. Calcd. for C₄₀H₄₉F₂N₈O₆ 775.3743 found: 775.3740 (M + H)⁺

(1R,1′R)-2,2′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl((2S,4R)-4-fluoro- 2,1-pyrrolidinediyl)))- bis(N,N-diethyl-2-oxo-1-phenylethanamine) RT = 8.13 min, method I LCMS: Anal. Calcd. forC₅₀H₅₆F₂N₈O₂ 839.04 found: 839.46 (M + H)⁺ HRMS: Anal. Calcd. forC₅₀H₅₇F₂N₈O₂ 839.4572 found: 839.4543 (M + H)⁺

Synthesis of JG-18 as in Example 28 Step a Using Hydroxyproline in Placeof Proline

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.89 (2H, t, J=8.39 Hz) 7.74 (2H, t,J=8.24 Hz) 7.28-7.37 (5H, m) 5.01-5.08 (3H, m) 4.27-4.57 (4H, m)3.44-3.53 (1H, m) 3.37 (1H, d, J=10.99 Hz) 2.12 (1H, d, J=11.60 Hz) 1.93(1H, dd, J=12.05 Hz, 6.56 Hz)

LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10%water 0.1% TFA mobile phase, t_(R)=3.62 min, Anal Calcd. forC₂₁H₂₁BrN₂O₅ 461.32. found 462.64 (M+H)⁺.

Synthesis of JG-19 from JG-18 as in Example 28 Step b

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=1.88 min, Anal.Calcd. for C₂₁H₂₀BN₃O₃ 441.07. found 442.22 (M+H)⁺

(2S,4R)-benzyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate(1.5 g, 3.4 mmol) was added as a solid to a solution ofbis(2-methoxyethyl)aminosulfur trifluoride (0.98 mL, 5.1 mmol) in 15 mLCH₂Cl₂ cooled to −78° C. Reaction was stirred at −78° C. for two hoursand then warmed to room temperature and stirred for 2 hours. Reactionwas poured into saturated sodium bicarbonate solution and stirred untilbubbling ceased. Layers were separated and aqueous layer washed one timewith CH₂Cl₂. Combined organics were washed with brine, dried (MgSO₄),filtered, and concentrated to give a yellow oil. The oil was trituratedwith CH₂Cl₂ and pentane to yield (2S,4S)-benzyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylateJG-20 as a yellow solid (0.96 g, 62%).

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.70 (2H, d, J=7.02 Hz) 7.48-7.55 (3H,m) 7.41-7.35 (3H, m) 7.19-7.11 (2H, m) 5.15-5.02 (3H, m) 3.84-3.78 (2H,m) 3.33 (2H, s) 2.53-2.61 (1H, m) 2.33-2.42 (1H, m)

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=2.10 min, Anal.Calcd. for C₂₁H₁₉Br₁F₁N₃O₂ 443.06. found 444.05 (M+H)⁺

(2S,4R)-tert-butyl4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate,1-2c (1.5 g, 3.3 mmol) was added as a solid to a solution ofbis(2-methoxyethyl)aminosulfur trifluoride (0.91 mL, 5.0 mmol) in 15 mLCH₂Cl₂ cooled to −78° C. Reaction was stirred at −78° C. for two hoursand then warmed to room temperature and stirred for 2 hours. Reactionwas poured into saturated sodium bicarbonate solution and stirred untilbubbling ceased. Layers were separated and aqueous layer washed one timewith CH₂Cl₂. Combined organics were washed with brine, dried (MgSO₄),filtered, and concentrated to give a brown oil. The oil waschromatographed on silica gel with 5% MeOH/CH₂Cl₂ to yield4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenylboronicacid as a tan solid (0.46 g, 37%).

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=1.46 min, Anal.Calcd. for C₁₈H₂₃B₁F₁N₃O₄ 375.18. found 376.12 (M+H)⁺

JG-22 is synthesized from JG-20 and JG-21 as described in Example 28step c.

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=2.27 min, Anal.Calcd. for C₃₉H₄₀F₂N₆O₄ 694.31. found 695.35 (M+H)⁺

JG-23 is synthesized from JG-22 as described in Example 28 step d.

LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10%water 0.1% TFA mobile phase, t_(R)=2.62 min, Anal Calcd. forC₃₁H₃₄F₂N₆O₂ 560.27. found 561.52 (M+H)⁺.

JG-24 is synthesized from JG-22 and Cap-2 as in Example 28 step e.

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=2.30 min, Anal.Calcd. for C₄₁H₄₅F₂N₇O₃ 721.36. found 722.42 (M+H)⁺

JG-25 is synthesized from JG-24 via reaction with methanolic HCl asdescribed in Example LS14 step b.

LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minutehold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95%acetonitrile, 5% water, 10 mm ammonium acetate, t_(R)=1.98 min, Anal.Calcd. for C₃₆H₃₇F₂N₇O₁ 621.30. found 622.48 (M+H)⁺

Section OL LC Conditions:

Condition 1: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flowrate: 4 ml/min; 0% B to 100% B over 3 min with a 1 min hold time.

Condition 2: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flowrate: 4 ml/min; 0% B to 100% B over 2 min with a 1 min hold time

Condition 3: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flowrate: 4 ml/min; 0% B to 100% B over 4 min with a 1 min hold time

Condition 4: Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90%MeOH/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 4 min witha 1 min hold time

Condition 5: Solvent A: 5% acetonitrile/95% water/10 mmol ammoniumacetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate;Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flowrate: 4 ml/min; 0% B to 100% B over 9 min with a 1 min hold time

Condition 6: Solvent A: 10% MeOH/90% water/0.2% H₃PO₄; Solvent B: 90%MeOH/10% water/0.2% H₃PO₄; Column: Phenomenex 5u C-18 4.6×50 mm;Wavelength: 220 nM; Flow rate: 1.5 ml/min; 0% B to 100% B over 14 minwith a 3 min hold time

Condition 7: Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90%MeOH/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 3 min witha 1 min hold time

Condition 8: Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90%MeOH/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm;Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 2 min witha 1 min hold time

Experimentals Caps:

Step a: Dimethylcarbamoyl chloride (0.92 mL, 10 mmol) was added slowlyto a solution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride(2.44 g; 10 mmol) and Hunig's base (3.67 mL, 21 mmol) in THF (50 mL).The resulting white suspension was stirred at room temperature overnight(16 hours) and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The resulting yellow oil was purified by flashchromatography, eluting with ethyl acetate:hexanes (1:1). Collectedfractions were concentrated under vacuum providing 2.35 g (85%) ofIntermediate Cap OL-1 as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.84 (d, J=6.95 Hz, 3H) 0.89 (d, J=6.59 Hz, 3H) 1.98-2.15 (m, 1H) 2.80(s, 6H) 5.01-5.09 (m, J=12.44 Hz, 1H) 5.13 (d, J=12.44 Hz, 1H) 6.22 (d,J=8.05 Hz, 1H) 7.26-7.42 (m, 5H). LC (Cond. 1): RT=1.76 min; MS: Anal.Calcd. for [M+H]⁺ C₁₆H₂₂N₂O₃: 279.17. found 279.03.

Step b: To Intermediate Cap OL-1 (2.35 g; 8.45 mmol) in 50 ml MeOH wasadded Pd/C (10%; 200 mg) and the resulting black suspension was flushedwith N₂ (3×) and placed under 1 atm of H₂. The mixture was stirred atroom temperature overnight and filtered though a microfiber filter toremove the catalyst. The resulting clear solution was then concentratedunder reduced pressure to obtain 1.43 g (89%) of Cap OL-2 as a whitefoam, which was used without further purification. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.87 (d, J=4.27 Hz, 3H) 0.88 (d, J=3.97 Hz, 3H) 1.93-2.11(m, 1H) 2.80 (s, 6H) 3.90 (dd, J=8.39, 6.87 Hz, 1H) 5.93 (d, J=8.54 Hz,1H) 12.36 (s, 1H).). LC (Cond. 1): RT=0.33 min; MS: Anal. Calcd. for[M+H]⁺ C₈H₁₇N₂O₃: 1898.12. found 189.04.

Cap OL-3 was prepared from (S)-benzyl 2-aminopropanoate hydrochlorideaccording to the method described for Cap OL-2. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.27 (d, J=7.32 Hz, 3H) 2.80 (s, 6H) 4.06 (qt, 1H) 6.36(d, J=7.32 Hz, 1H) 12.27 (s, 1H). LC (Cond. 1): RT=0.15 min; MS: Anal.Calcd. for [M+H]⁺ C₆H₁₃N₂O₃: 161.09. found 161.00.

Cap OL-4 was prepared from (S)-tert-butyl 2-amino-3-methylbutanoatehydrochloride and 2-fluoroethyl chloroformate according to the methoddescribed for Cap-47. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t, J=6.71 Hz,6H) 1.97-2.10 (m, 1H) 3.83 (dd, J=8.39, 5.95 Hz, 1H) 4.14-4.18 (m, 1H)4.20-4.25 (m, 1H) 4.50-4.54 (m, 1H) 4.59-4.65 (m, 1H) 7.51 (d, J=8.54Hz, 1H) 12.54 (s, 1H)

Cap OL-5 was prepared from (S)-diethyl alanine and methyl chloroformateaccording to the method described for Cap-51. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.72-0.89 (m, 6H) 1.15-1.38 (m, 4H) 1.54-1.66 (m, 1H) 3.46-3.63(m, 3H) 4.09 (dd, J=8.85, 5.19 Hz, 1H) 7.24 (d, J=8.85 Hz, 1H) 12.55 (s,1H). LC (Cond. 2): RT=0.66 min; MS: Anal. Calcd. for [M+H]⁺ C₉H₁₈NO₄:204.12. found 204.02.

New Examples

The following analogs were prepared from 1e in similar fashion to thepreparation of Example 1 and employing the appropriate Cap.

Ex- am- ple Num- ber Compound Name Structure Analytical Data OL-13-((1S)-1-(((2S)-2-(4-(4′- (2-((2S)-1-((2S)-2- ((dimethylcarbamoyl)-amino)-3-methyl- butanoyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)-1,1- dimethylurea

LC/MS: 2.16 min (Cond'n 3); Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₁₀O₄:765.45; found 765.47. OL-2 3-((1S)-2-((2S)-2-(4-(4′- (2-((2S)-1-(N-(dimethylcarbamoyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-1,1- dimethylurea

LC/MS: 1.86 min (Cond'n 3); Anal. Calcd. for [M + H]⁺ C₃₈H₄₉N₁₀O₄:709.39; found 709.43. OL-3 2-fluoroethyl ((1S)-1- (((2S)-2-(4-(4′-(2-((2S)-1- ((2S)-2-(((2- fluoroethoxy)carbonyl)- amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidaozl-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

LC/MS: 2.83 min (Cond'n 4); Anal. Calcd. for [M + H]⁺ C₄₂H₅₃F₂N₈O₆:803.40; found 803.47. OL-4 methyl ((1S)-2-ethyl-1- (((2S)-2-(4-(4′-(2-((2S)-1- ((2S)-3-ethyl-2- ((methoxycarobnyl)- amino)pentanoyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)- butyl)carbamate

LC/MS: 2.64 min (Cond'n 3); Anal. Calcd. for [M + H]⁺ C₄₄H₅₉N₈O₆:795.45; found 795.48. OL-5 1,1′-(4,4′- biphenyldiylbis(1H-imidazole-4,2-diyl(2S)- 2,1-pyrrolidinediyl((2S)- 3-methyl-1-oxo-1,2-butane- diyl)))ditetrahydro- 2(1H)-pyrimidinone

LC/MS: 2.95 min (Cond'n 4); Anal. Calcd. for [M + H]⁺ C₄₄H₅₇N₁₀O₆:789.46; found 789.52. OL-6 methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)- amino)-4-methyl-pentanoyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)-3-methylbutyl)carbamate

LC/MS: 2.95 min (Cond'n 3); Anal. Calcd. for [M + H]⁺ C₄₂H₅₃N₈O₆:767.42; found 767.43.

Example OL-7 methyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example OL-7 was prepared from 1-2e-3 in similar fashion to thepreparation of Example 1, using Cap-51 as the coupling partner. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.80 (dd, J=6.41, 2.44 Hz, 12H) 1.87-1.98 (m,2H) 2.79-2.91 (m, 2H) 3.01-3.13 (m, 2H) 3.54 (s, 6H) 3.98 (t, J=7.93 Hz,2H) 4.22-4.37 (m, 2H) 4.52 (t, J=14.19 Hz, 2H) 5.31 (t, J=8.39 Hz, 2H)7.50 (d, J=7.93 Hz, 2H) 7.82-7.87 (m, 4H) 7.88-7.97 (m, 6H) 8.08 (s,2H). LC (Cond'n 6): 7.64 min; MS: Anal. Calcd. for [M+H]⁺ C₄₀H₄₇F₄N₈O₆:811.35. found 811.46. HRMS: Anal. Calcd. for (M+H)⁺ C₄₀H₄₇F₄N₈O₆811.3549 found 811.3553.

The following analogs were prepared from 1-2e-3 in similar fashion tothe preparation of Example 1 and employing the appropriate Cap.

Ex- am- ple Num- ber Compound Name Structure Analytical Data OL-8(1R,1′R)-2,2′-(4,4′- biphenyldiylbis(1H- imidazole-4,2- diyl((2S)-4,4-difluoro-2,1- pyrrolidinediyl)))- bis(N,N-dimethyl-2- oxo-1-phenylethanamine)

LC/MS: 3.98 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₄₆H₄₇F₄N₈O₂:819.37; found 819.78. OL-9 (1R,1′R)-2,2′-(4,4′- biphenyldiylbis(1H-imidazole-4,2- diyl((2S)-4,4- difluoro-2,1- pyrrolidinediyl)))-bis(N,N-diethyl-2- oxo-1- phenylethanamine)

LC/MS: 4.58 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₅₀H₅₅F₄N₈O₂:875.449; found 875.90. OL-10 methyl ((1S,2R)-1- (((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro- 1-(N- (methoxycarbonyl)- O-methyl-L- threonyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-4,4-difluoro-1- pyrrolidinyl)carbon yl)-2- methoxy propyl)- carbamate

LC/MS: 2.18 min (Cond'n 7); Anal. Calcd. for [M + H]⁺ C₄₀H₄₇F₄N₈O₈:843.84; found 844.04. OL-11 methyl ((1S)-2- ((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro- 1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-4,4-difluoro-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

LC/MS: 2.04 min (Cond'n 7); Anal. Calcd. for [M + H]⁺ C₃₆H₃₉F₄N₈O₆:755.29; found 755.78.

The following analogs were prepared from 1-3e in similar fashion to thepreparation of Example 1 and employing the appropriate Cap.

Ex- am- ple Num- ber Compound Name Structure Analytical Data OL-12methyl ((1S)-1- (((2S)-2-(4-(4′-(2- ((2S)-4,4-difluoro-1- ((2S)-2-((methoxycarbonyl)- amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-carbonyl)-2- methylpropyl) carbamate

LC/MS: 2.33 min (Cond'n 3); Anal. Calcd. for [M + H]⁺ C₄₀H₄₉F₂N₈O₂:775.37; found 775.37. OL-13 rac-(1R)-2-((2S)-2- (4-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-4,4- difluoro-2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N- diethyl-2-oxo-1- phenylethanamine

LC/MS: 3.93 min (Cond'n 5); Anal. Calcd. for [M + H]⁺ C₅₀H₅₇F₂N₈O₂:839.40; found 839.93.

Example OL-19 methyl((1S)-1-(((2R,3S)-3-hydroxy-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Step a: Intermediate OL-15 was prepared in similar fashion asintermediate 1a, where N-Boc-L-proline was substituted forN-Boc-trans-3-hydroxy-L-proline. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.34/1.4) (2 br. s., 9H) 1.65-1.77 (m, 1H) 1.83-1.95 (m, 1H) 3.33-3.42(m, 1H) 3.43-3.51 (m, 1H) 3.96-4.07 (m, 1H) 4.16 (s, 1H) 4.44-4.65 (m,2H) 5.22-5.28 (m, 1H) 7.74 (d, J=8.54 Hz, 2H) 7.86-7.94 (m, 2H)8.15-8.32 (m, 1H). LC (Cond. 4): RT=3.33 min; MS: Anal. Calcd. for[2M+Na]⁺ C₃₆H₄₆Br₂N₄NaO₁₀: 877.57. found 877.11.

Step b: Intermediate OL-16 was prepared from intermediate OL-15 insimilar fashion as intermediate 1b. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.16/1.39 (2 br. s., 9H) 1.71-1.81 (m, J=6.10 Hz, 1H) 2.01-2.17 (m, 1H)3.37-3.50 (m, 1H) 3.50-3.62 (m, 1H) 4.15 (s, 1H) 4.49-4.70 (m, 1H) 5.36(dd, J=6.71, 3.66 Hz, 1H) 7.44-7.62 (m, 3H) 7.68 (d, J=7.02 Hz, 2H)11.96/11.99/12.26/12.30 (m, 1H). LC (Cond. 8): RT=1.87 min; MS: Anal.Calcd. for [M+H]⁺ C₁₈H₂₃BrN₃O₃: 408.08. found 408.09.

Step c: Intermediate OL-17 was prepared by coupling intermediate OL-16with 1c in similar fashion to the preparation of 1d. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.09-1.49 (m, 18H) 1.71-2.04 (m, 4H) 2.06-2.28 (m, 2H)3.33-3.40 (m, 1H) 3.41-3.65 (m, 3H) 4.18 (s, 1H) 4.52-4.69 (m, 1H)4.70-4.88 (m, 1H) 5.38 (s, 1H) 6.64-7.35 (m, 1H) 7.39-7.96 (m, 9H)11.71-12.0/12.10-12.36 (m, 2H). LC (Cond. 2): RT=1.36 min; MS: Anal.Calcd. for [M+H]⁺ C₃₆H₄₅N₆O₅: 641.77. found 641.39.

Step d: Intermediate OL-18 was prepared by deprotection of intermediateOL-17 with HCl in similar fashion to the preparation of 1-1e. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.92-2.07 (m, 2H) 2.14-2.25 (m, 1H) 2.35-2.44(m, 1H) 3.15 (s, 4H) 3.32-3.41 (m, J=7.02, 7.02, 7.02 Hz, 1H) 3.41-3.51(m, J=7.32 Hz, 2H) 3.54-3.66 (m, 1H) 4.68 (d, J=4.27 Hz, 1H) 4.78-4.89(m, J=4.88 Hz, 1H) 5.04 (s, 1H) 6.89/7.73 (2d, J=8.70 Hz, 1H) 7.89 (dd,J=8.24, 4.58 Hz, 4H) 7.96-8.07 (m, 4H) 8.15 (d, J=23.19 Hz, 2H)9.62-10.12 (m, 2H) 10.21-10.74 (m, 2H).). LC (Cond. 8): RT=1.30 min; MS:Anal. Calcd. for [M+H]⁺ C₂₆H₂₉N₆O: 441.24. found 441.18.

Step e: Example OL-19 was prepared by coupling of intermediate OL-18with Cap-51 in similar fashion to the preparation of Example 1. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.78 (d, J=6.41 Hz, 6H) 0.83 (d, J=6.71 Hz, 6H)1.92-2.12 (m, 5H) 2.12-2.21 (m, 1H) 2.31 (dd, J=12.21, 5.80 Hz, 1H)2.35-2.43 (m, 1H) 3.54 (d, J=4.27 Hz, 6H) 3.78-3.89 (m, 3H) 3.91-4.02(m, 1H) 4.07-4.19 (m, 2H) 4.36-4.50 (m, 1H) 4.81 (d, J=3.66 Hz, 1H) 5.13(t, J=7.17 Hz, 1H) 5.79 (s, 1H) 7.34 (dd, J=11.29, 8.85 Hz, 2H)7.83-7.90 (m, 4H) 7.90-8.01 (m, 4H) 8.12 (s, 2H) [Note: the signal forthe imidazole NH was too broad to assign a chemical shift].). LC (Cond.4): RT=2.76 min; MS: Anal. Calcd. for [M+H]⁺ C₄₀H₅₁N₈O₇: 755.39. found755.38. HRMS: Anal. Calcd. for (M+H)^(+C) ₄₀H₅₁N₈O₇ 755.3881 found755.3873.

The following analog was prepared from intermediate OL-18 in similarfashion to the preparation of Example 1 and employing Cap-52.

Ex- am- ple Num- ber Compound Name Structure Analytical Data OL-20methyl ((1S)-2-((2S)-2- (4-(4′-(2-((2R,3S)-3- hydroxy-1-(N-(methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

LC/MS: 2.32 min (Cond'n 4); Anal. Calcd. for [M + H]⁺ C₃₆H₄₃N₈O₇:699.78; found 699.32.

The following analog was prepared in similar fashion to the preparationof OL-19 but using N-Boc-cis-3-hydroxy-L-proline as starting material.

Ex- am- ple Num- Analytical ber Compound Name Structure Data OL- 21methyl ((1S)-1-(((2R)-3- hydroxy-2-(4-(4′-(2- ((2S)-1-((2S)-2-((methoxycarbonyl)- amino)-3-methyl- butanoyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

LC/MS: 2.74 min (Cond'n 4); Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₇:755.39; found 755.34. Analytical Data Ex- (Cond 1: 3 min am- gradient,ple 4 min run; Num- Cond 2: 2 min ber Compound Name Heterocycles withNew Caps gradient, 3 min run) D71 tert-butyl (2S)-2-(5-(2-(4-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H-imidazol-2-yl)-1- pyrrolidine- carboxylate

t_(R) = 1.82 min, (97.7%), (Cond 1) LRMS: Anal. Calcd. for C₄₁H₅₀N₉O₃716.40; found: 716.44 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₅₀N₉O₃716.4037; found: 716.4056 (M + H)⁺. D72 (1R)-N,N-diethyl-2-oxo-1-phenyl-2- ((2S)-2-(5-(4-(5-(2- ((2S)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2- pyrimidinyl)- phenyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)- ethanamine

t_(R) = 1.56 min, (~95.3%, has shoulder), (Cond 1) LRMS: Anal. Calcd.for C₃₆H₄₂N₉O 616.35; found: 616.37 (M + H)⁺. HRMS: Anal. Calcd. forC₃₆H₄₂N₉O 616.3512; found: 616.3540 (M + H)⁺. D73 methyl ((1S)-2-((2S)-2-(5-(4-(5-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimi- dinyl)phenyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)- 1-methyl-2- oxoethyl)carbamate

t_(R) = 1.52 min, (96.2%), (Cond 1) LRMS: Anal. Calcd. for C₃₄H₄₁N₁₀O₆685.32; found: 685.21 (M + H)⁺. HRMS: Anal. Calcd. for C₃₄H₄₁N₁₀O₆685.3211; found: 685.3196 (M + H)⁺. D74 methyl ((1S)-1-(((2S)-2-(5-(2-(4- (2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- carbonyl)-2-methylpropyl)- carbamate

t_(R) = 2.09 min, (95%), (Cond 1) LRMS: Anal. Calcd. for C₃₈H₄₉N₁₀O₆741.38; found: 741.26 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₉N₁₀O₆741.3837; found: 741.3824 (M + H)⁺. D75 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(2-(4-(2- ((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl)amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate

t_(R) = 1.98 min, (95%), (Cond 1) LRMS: Anal. Calcd. for C₃₈H₄₅N₁₀O₆737.35; found: 737.22 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₅N₁₀O₆737.3524; found: 737.3555 (M + H)⁺. D76 methyl ((1S)-1-(((2S)-2-(5-(2-(4-(2- ((2S)-1-((2R)-2- (diethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)- phenyl)-5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)- carbonyl)-2-methyl-propyl)carbamate

t_(R) = 1.69 min, (95%), (Cond 1) LRMS: Anal. Calcd. for C₄₃H₅₃N₁₀O₄773.43; found: 773.30 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₅₃N₁₀O₄773.4251; found: 773.4280 (M + H)⁺. D77 methyl ((1S)-2-((2S)-2-(5-(2-(4-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.81 min, (97.5%), (Cond 1) LRMS: Anal. Calcd. for C₄₁H₄₉N₁₀O₄745.39; found: 745.27 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₉N₁₀O₄745.3938; found: 745.3939 (M + H)⁺.Section J

Ex- am- ple Num- ber Compound Name Structure Analytical Data J.1a

t_(R) = 1.7 min, (Cond 2); LCMS: C₁₀H₉BrO₃ found: 257 (M + H)⁺. J.1b

t_(R) = 1.9 min, (Cond 2); LCMS: C₁₁H₁₁BrO₃ found: 271 (M + H)⁺. J.1c

t_(R) = 2.1 min, (Cond 2); LCMS: C₁₆H₁₃BrO₃ found: 332 (M + H)⁺. J1

t_(R) = 2.2 min, (Cond 2); LCMS: C₂₀H₂₄BrNO₇ found: 470 (M + H)⁺. J2

t_(R) = 2.2 min, (Cond 2); LCMS: C₂₁H₂₆BrNO₇ found: 484 (M + H)⁺. J3

t_(R) = 2.3 min, (Cond 2); LCMS: C₂₆H₂₈BrNO₇ found: 546 (M + H)⁺. J4

t_(R) = 1.84 min, (100%) (Cond 2); LRMS: Anal. Calcd. for C₂₀H₂₄BrN₃O₄;450.10; found: 450.13 and 452.13 (M + H)⁺. J5

t_(R) = 1.93 min, (99%) (Cond 2); Reported in J5. J6

t_(R) = 2.1 min, (93%) (Cond 2); LRMS: Anal. Calcd. for C₂₆H₂₉BrN₃O₄526.13; found: 526.16 and 528.16 (M + H)⁺. J7

t_(R) = 1.7 min, (100%) (Cond 2); Reported in J7. J8 methyl 2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(tert-butoxocarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazole-4- carboxylate

t_(R) = 1.70 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C₃₈H₄₇N₆O₆683.36; found: 683.42 (M + H)⁺. J9 ethyl 2-((2S)-1- (tert-butoxycarbonyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(tert-butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazole-4- carboxylate

t_(R) = 1.78 min, (97.5%) (Cond 2); LRMS: Anal. Calcd. for C₃₉H₄₉N₆O₆697.37; found: 697.38 (M + H)⁺. J10 benzyl 2-((2S)-1- (tert-butoxycarbonyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(tert-butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazole-4- carboxylate

t_(R) = 1.88 min, (85%) (Cond 2); LRMS: Anal. Calcd. for C₄₄H₅₁N₆O₆759.39; found: 759.48 (M + H)⁺. J11 tert-butyl (2S)-2-(5-(4′-(2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-4- (methylcarbamoyl)- 1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

t_(R) = 1.65 min, (90%) (Cond 2); LRMS: Anal. Calcd. for C₃₈H₄₈N₇O₅682.37; found: 682.42 (M + H)⁺. J11.a

t_(R) = 1.60 min, (Cond 2); LCMS: C₃₇H₄₆N₇O₅ found: 668 (M + H)⁺. J12

t_(R) = 1.25 min, (97%) (Cond 2); LCMS: C₂₈H₃₁N₆O₂ found: 483 (M + H)⁺.J13

t_(R) = 1.34 min, (Cond 2); LCMS: C₂₉H₃₃N₆O₂ found: 497 (M + H)⁺. J14

t_(R) = 1.51 min, (90%) (Cond 2); LCMS: C₃₄H₃₅N₆O₂ found: 559 (M + H)⁺.J15

t_(R) = 1.32 min, (99%) (Cond 2); LCMS: C₂₈H₃₂N₇O found: 482 (M + H)⁺.J15.a

t_(R) = 1.07 min, (98%) (Cond 2); LCMS: C₂₇H₃₀N₇O found: 468 (M + H)⁺.J16 methyl 2-((2S)-1- ((2R)-2- ((methoxycarbonyl) amino)-2-phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate

t_(R) = 1.62 min, (99.5%) (Cond 2); LRMS: Anal. Calcd. for C48H49N8O8865.37; found: 865.34 (M + H)⁺. HRMS: Anal. Calcd. for C48H49N8O8865.3673; found: 865.3715 (M + H)⁺. J17 methyl 2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.37 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C48H53N8O4804.42; found: 805.51 (M + H)⁺. HRMS: Anal. Calcd. for C48H53N8O4805.4190; found: 805.4211 (M + H)⁺. J18 methyl 2-((2S)-1-((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.46 min, (94%) (Cond 2); LRMS: Anal. Calcd. for C54H61N8O6885.48; found: 885.48 (M + H)⁺. HRMS: Anal. Calcd. for C54H61N8O6885.4816; found: 885.4852 (M + H)⁺. J19 ethyl 2-((2S)-1- ((2R)-2-((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.68 min, (99%) (Cond 2); LRMS: Anal. Calcd. for C49H51N8O8879.38; found: 879.37 (M + H)⁺. HRMS: Anal. Calcd. for C49H51N8O8879.3830; found: 879.3814 (M + H)⁺. J20 ethyl 2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.45 min, (89%) (Cond 2); LRMS: Anal. Calcd. for C49H55N8O4818.44; found: 818.40 (M + H)⁺. HRMS: Anal. Calcd. for C49H55N8O4819.4346; found: 819.4340 (M + H)⁺. J21 benzyl 2-((2S)-1- ((2R)-2-((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.80 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C54H53N8O8941.40; found: 941.39 (M + H)⁺. HRMS: Anal. Calcd. for C54H53N8O8941.3986; found: 941.4033 (M + H)⁺. J22 benzyl 2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.56 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C54H57N8O4881.45; found: 881.46 (M + H)⁺. HRMS: Anal. Calcd. for C54H57N8O4881.4503; found: 881.4536 (M + H)⁺. J23 benzyl 2-((2S)-1-((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

t_(R) = 1.63 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C60H65N8O4961.51; found: 961.54 (M + H)⁺. HRMS: Anal. Calcd. for C60H65N8O4961.5129; found: 961.5164 (M + H)⁺. J24 benzyl 2-((2S)-1- (N-(methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(N-(methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazole-4- carboxylate

t_(R) = 1.64 min, (94%) (Cond 2); LRMS: Anal. Calcd. for C44H49N8O8817.37; found: 817.38 (M + H)⁺. HRMS: Anal. Calcd. for C44H49N8O8817.3673; found: 817.3675 (M + H)⁺. J25 methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4-(methylcarbamoyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxo-1-phenylethyl)carba- mate

t_(R) = 1.58 min, (99.6%) (Cond 2); LRMS: Anal. Calcd. for C48H50N9O7864.38; found: 864.47 (M + H)⁺. HRMS: Anal. Calcd. for C48H50N9O7864.3833; found: 864.3849 (M + H)⁺. J26 2-((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-N- methyl-1H-imidazole-4- carboxamide

t_(R) = 1.31 min, (93.2%) (Cond 2); LRMS: Anal. Calcd. for C48H54N9O3804.44; found: 804.51 (M + H)⁺. HRMS: Anal. Calcd. for C48H54N9O3804.4350; found: 804.4369 (M + H)⁺. J27 N-methyl-2-((2S)-1-((2R)-2-phenyl- 2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxamide

t_(R) = 1.39 min, (95.4%) (Cond 2); LRMS: Anal. Calcd. for C54H62N9O3884.50; found: 884.52 (M + H)⁺. HRMS: Anal. Calcd. for C54H62N9O3884.4976; found: 884.4973 (M + H)⁺. J28 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-4- (methylcarbamoyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.34 min, (89.3%) (Cond 2); LRMS: Anal. Calcd. for C38H46N9O7740.35; found: 740.31 (M + H)⁺. HRMS: Anal. Calcd. for C38H46N9O7740.3520; found: 740.3597 (M + H)⁺. J29 methyl ((1R)-2- ((2S)-2-(4-carbamoyl-5-(4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carba- mate

t_(R) = 1.55 min, (96.4%) (Cond 2); LRMS: Anal. Calcd. for C47H48N9O7740.35; found: 740.31 (M + H)⁺. HRMS: Anal. Calcd. for C47H48N9O7740.3520; found: 740.3497 (M + H)⁺. J30 2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylic acid

t_(R) = 1.52 min, (92.8%) (Cond 2); LRMS: Anal. Calcd. for C47H47N8O8851.35; found: 851.37 (M + H)⁺. HRMS: Anal. Calcd. for C47H47N8O8851.3517; found: 851.3553 (M + H)⁺. J31 2-((2S)-1-((2R)-2- phenyl-2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)-5- (4′-(2-((2S)-1-((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylic acid

t_(R) = 1.36 min, (96.5%) (Cond 2); LRMS: Anal. Calcd. for C53H59N8O4871.147; found: 871.47 (M + H)⁺. HRMS: Anal. Calcd. for C53H59N8O4871.4659; found: 871.4692 (M + H)⁺. J32

t_(R) = 1.96 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C₁₁H₁₁BrF₃N₂O323.00; found: 323.05 and 325.05 (M + H)⁺. ¹H NMR (300 MHz, DMSO-d₆) δ7.58 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 3.06 (s, 6 H).J32.a

t_(R) = 2.19 min, (96%) (Cond 2); Reported in J32.a J32.b

t_(R) = 2.3 min, (73%) (Cond 2); LCMS: C₂₅H₃₄BF₃N₃O₄ found: 508 (M +H)⁺. J33 tert-butyl (2S)-2- (5-(4′-(2-((2S)-1- (tert- butoxycarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)- 1-pyrrolidine- carboxylate

t_(R) = 2.7 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C₃₇H₄₄F₃N₆O₄693.34; found: 693.33 (M + H)⁺. HRMS: Anal. Calcd. for C₃₇H₄₄F₃N₆O₄693.3376; found: 693.3370 (M + H)⁺. J33.a tert-butyl (2S)-2-(5-(4′-(2-((1S)-1- ((tert- butoxycarbonyl)(meth- yl)amino)ethyl)-1H-imidazol-5-yl)- 4-biphenylyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)- 1-pyrrolidine- carboxylate

t_(R) = 1.97 min, (97%) (Cond 2); LRMS: Anal. Calcd. for C₃₆H₄₄F₃N₆O₄681.34; found: 681.31 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₄F₃N₆O₄681.3376; found: 681.3383 (M + H)⁺. J34 tert-butyl (2S)-2-(5-(4′-(2-((2S)-1- ((benzyloxy)carbon- yl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)- 1- pyrrolidinecarboxyl- ate

t_(R) = 2.0 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C₄₀H₄₂F₃N₆O₄727.32; found: 727.19 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₂F₃N₆O₄727.3220; found: 727.3251 (M + H)⁺. J34.a tert-butyl (2S)-2-(5-(4-(5-(2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4- (trifluoromethyl)-1H-imidazol-2-yl)- 1- pyrrolidinecarboxyl- ate

t_(R) = 1.97 min, (93%) (Cond 2); LRMS: Anal. Calcd. for C₃₅H₄₂F₃N₈O₄695.33; found: 695.28 (M + H)⁺. J35

t_(R) = 1.46 min, (92%) (Cond 2); LCMS: C₂₇H₂₈F₃N₆O found: 493 (M + H)⁺.J35.a

LCMS: C₂₆H₂₈F₃N₆ found: 481 (M + H)⁺. J36

LCMS: C₃₅H₃₄F₃N₆O₂ found: 626 (M + H)⁺. J36.a

t_(R) = 1.45 min. (Cond 2); LCMS: C₂₅H₂₆F₃N₈ found: 495 (M + H)⁺. J37methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethyl)- carbamate

t_(R) = 1.9 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C₄₇H₄₆F₃N₈O₄875.35; found: 875.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₇H₄₆F₃N₈O₄875.3492; found: 875.3504 (M + H)⁺. J38 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-4- (trifluoromethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.7 min, (95.5%) (Cond 2); LRMS: Anal. Calcd. for C₃₇H₄₂F₃N₈O₆751.32; found: 751.32 (M + H)⁺. HRMS: Anal. Calcd. for C₃₇H₄₂F₃N₈O₆751.3179; found: 751.3163 (M + H)⁺. J39 methyl ((1S)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4-(trifluoromethyl)- 1H-imidaozl-2-yl)- 1- pyrrolidinyl)carbon yl)-2-methylpropyl)carba- mate

t_(R) = 1.9 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C₄₁H₅₀F₃N₈O₆807.38; found: 807.33 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₅₀F₃N₈O₆807.3805; found: 807.3773 (M + H)⁺. J40 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)- N,N-diethyl-2-oxo- 1-phenylethanamine

t_(R) = 1.6 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C₅₁H₅₈F₃N₈O₂871.46; found: 871.48 (M + H)⁺. HRMS: Anal. Calcd. for C₅₁H₅₈F₃N₈O₂871.4635; found: 871.4647 (M + H)⁺. J41 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl)amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxoethyl)carbamate

t_(R) = 1.8 min, (96.9%) (Cond 2); LRMS: Anal. Calcd. for C₄₁H₄₆F₃N₈O₆803.35; found: 803.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₆F₃N₈O₆803.3492; found: 803.3507 (M + H)⁺. J42 methyl ((1S,2R)-2-methoxy-1-(((2S)- 2-(5-(4′-(2-((2S)-1- (N- (methoxycarbonyl)-O-methyl-L- threonyl)-2- pyrrolidinyl)-4- (trifluoromethyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbon- yl)propyl)carbamate

t_(R) = 1.8 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C₄₁H₅₀F₃N₈O₈839.37; found: 839.30 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₅₀F₃N₈O₈839.3704; found: 839.3677 (M + H)⁺. J42.a methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((1S)-1-((N- (methoxycarobnyl)- L-alanyl)(methyl)ami- no)ethyl)-1H- imidazol-5-yl)-4- biphenylyl)-4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

t_(R) = 1.69 min, (100%) (Cond 2); LRMS: Anal. Calcd. for C₃₆H₄₂F₃N₈O₆739.32; found: 739.31 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₂F₃N₈O₆739.3179; found: 739.3195 (M + H)⁺. J43 benzyl (2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-4-(trifluoromethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinecarboxyl- ate

t_(R) = 1.9 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C₄₀H₄₁F₃N₇O₅756.31; found: 756.19 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₁F₃N₇O₅756.3121; found: 756.3127 (M + H)⁺. J44

LCMS: C₃₂H₃₅F₃N₇O₃ found: 622 (M + H)⁺. J45 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.7 min, (93%) (Cond 2); LRMS: Anal. Calcd. for C₄₄H₅₀F₃N₈O₄811.39; found: 811.34 (M + H)⁺. HRMS: Anal. Calcd. for C₄₄H₅₀F₃N₈O₄811.3907; found: 811.3913 (M + H)⁺. J46 methyl ((1R)-2-((2S)-2-(5-(4-(5-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl)- 4- (trifluoromethyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1- phenylethyl)carba- mate

t_(R) = 1.82 min, (98%) (Cond 2); LRMS: Anal. Calcd. for C₄₅H₄₄F₃N₁₀O₆877.34; found: 877.29 (M + H)⁺. HRMS: Anal. Calcd. for C₄₅H₄₄F₃N₁₀O₆877.3397; found: 877.3403 (M + H)⁺. J47 (1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-diethyl-2-oxo- 1- phenylethanamine

t_(R) = 1.58 min, (97%) (Cond 2); LRMS: Anal. Calcd. for C₄₉H₅₆F₃N₁₀O₂873.44; found: 873.40 (M + H)⁺. HRMS: Anal. Calcd. for C₄₉H₅₆F₃N₁₀O₂873.4540; found: 873.4536 (M + H)⁺. J48 methyl ((1S)-1-(((2S)-2-(5-(2-(4- (2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-methylbutanoyl)-2- pyrrolidinyl)-4- (trifluoromethyl)- 1H-imidazol-5-yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon-yl)-2- methylpropyl)- carbamate

t_(R) = 1.85 min, (99%) (Cond 2); LRMS: Anal. Calcd. for C₃₉H₄₈F₃N₁₀O₆809.37; found: 809.37 (M + H)⁺. HRMS: Anal. Calcd. for C₃₉H₄₈F₃N₁₀O₆809.3710; found: 809.3683 (M + H)⁺. J49 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(4-(5-(2- ((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl)amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl)- 4- (trifluoromethyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

t_(R) = 1.75 min, (100%) (Cond 2); LRMS: Anal. Calcd. for C₃₉H₄₄F₃N₁₀O₆805.34; found: 805.34 (M + H)⁺. HRMS: Anal. Calcd. for C₃₉H₄₄F₃N₁₀O₆805.3397; found: 805.3384 (M + H)⁺. J50 methyl ((1S)-2-((2S)-2-(5-(4-(5-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

t_(R) = 1.61 min, (94%) (Cond 2); LRMS: Anal. Calcd. for C₃₅H₄₀F₃N₁₀O₆753.31; found: 753.31 (M + H)⁺. HRMS: Anal. Calcd. for C₃₅H₄₀F₃N₁₀O₆753.3084; found: 753.3099 (M + H)⁺. J51 (2R)-1-((2S)-2-(5-(4-(5-(2-((2S)-1- ((2R)-2- (diethylamino)prop anoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-diethyl-1-oxo- 2-propanamine

t_(R) = 1.41 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C₃₉H₅₂F₃N₁₀O₂749.42; found: 749.37 (M + H)⁺. HRMS: Anal. Calcd. for C₃₉H₅₂F₃N₁₀O₂749.4227; found: 749.4223 (M + H)⁺.

Cond 1: LCMS conditions: Phenomenex-Luna 4.6×50 mm S10 to 100% B over 3min, 4 min stop time, 4 mL/min, 220 nm, A: 10% MeOH—90% H₂O—0.1% TFA; B:90% MeOH—10% H₂O—0.1% TFA

Cond 2: LCMS conditions: Phenomenex-Luna 4.6×50 mm S10, 0 to 100% B over2 min, 3 min stop time, 4 mL/min, 220 nm, A: 10% MeOH—90% H₂O—0.1% TFA;B: 90% MeOH—10% H₂O—0.1% TFA

Example J2 (2S)-2-(1-(4-bromophenyl)-3-ethoxy-1,3-dioxopropan-2-yl)1-tert-butyl pyrrolidine-1,2-dicarboxylate

The ethyl 3-(4-bromophenyl)-3-oxopropanoate (15 g, 55 mmol) wasdissolved in CH₂Cl₂ (600 mL) and freshly recrystallized NBS (9.8 g, 55mmol) was added and the solution stirred 18 hr. The reaction mixture waswashed with NaHCO₃ solution, brine, and dried (MgSO₄), filtered, andconcentrated to give a residue which was not purified. Ethyl2-bromo-3-(4-bromophenyl)-3-oxopropanoate (16.5 g, 48 mmol) andN-Boc-L-proline (10 g, 48 mmol) were taken up in acetonitrile (450 mL)and Hunig's base (16 mL, 95 mmol) was added and the solution stirred 18hr. The solvent was removed by rotary evaporation and the residue takenup in ethyl acetate, washed with 0.1 N HCl, and brine. ¹H NMR (300 MHz,DMSO-d₆) δ 7.95 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 6.68-6.65 (m,1H), 4.39-4.30 (m, 1H), 4.21-4.12 (m, 2H), 2.27-2.21 (m, 1H), 2.0-1.95(m, 1H), 1.90-1.76 (m, 2H), 1.39 (s, 2H), 1.31 (s, 9H), 1.11 (t, J=7.3Hz, 3H).

LRMS: Anal. Calcd. for C₂₁H₂₆BrNO₇ 484.09. found: 410.08 (M+H)⁺.

Example J5 (S)-ethyl5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-4-carboxylate

A 1 L pressure bottle was charged with(2S)-2-(1-(4-bromophenyl)-3-ethoxy-1,3-dioxopropan-2-yl) 1-tert-butylpyrrolidine-1,2-dicarboxylate J2 (7 g, 35 mmol) and 11 g of NH₄OAc in125 mL of Xylene, and the reaction was heated at 140° C. for 3.5 hr.After being cooled, the solution was partition between ethyl acetate andwater. The organic layer was concentrated and the resultant residueapplied to a Biotage 40 m silica gel cartridge and eluted by 20-100%gradient, ethyl acetate/Hex to give 3 g (45%). ¹H NMR (300 MHz, CDCl₃) δ12.75 (br. s, 7.82), (br. s, 2H), 7.50 (d, J=8.4 Hz, 2H), 4.96-4.92 (m,1H), 4.23 (q, J=6.6 Hz, 2H), 3.68-3.50 (m, 1H), 3.40-3.32 (m, 1H),2.19-2.15 (m, 1H), 1.99-1.89 (m, 3H), 1.48/1.13 (s, 9H), 1.23 (t, J=7.3Hz, 3H). LRMS: Anal. Calcd. for C₂₁H₂₆BrN₃O₄ 464.12. found: 464.15 and466.15 (M+H)⁺.

Example J7 (S)-tert-butyl2-(5-(4-bromophenyl)-4-(methylcarbamoyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-ethyl5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-4-carboxylate(1 g, 2.1 mmol) was dissolved in 2M methylamine in MeOH (35 mL) andheated in a pressure vessel at 70° C. for 48 h. The reaction mixture wasconcentrated and the residue applied to a Biotage 25 m silica gelcartridge and eluted by 10-100% gradient, ethyl acetate/Hex to give 556mg (57%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.5 (br.s, 1H), 7.86-7.82 (m,1H), 7.77 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 4.83-4.70 (m, 1H),3.69-3.52 (br.s, 1H), 3.42-3.32 (m, 1H), 2.71 (d, 4.8 Hz, 3H), 2.30-1.78(m, 4H), 1.19-1.14 (m, 9H).

LRMS: Anal. Calcd. for C₂₀H₂₆BrN₄O₃ 449.12. found: 449.15 and 451.14(M+H)⁺.

Example J11.a

Entry J9 (1.1 g, 1.58 mmol) was taken up in ethanol (60 mL), 28%concentrated ammonium hydroxide soln (10 mL) was added, and the reactionheated in a pressure vessel at 75° C. for 48 h. The solvent was removedby rotary evaporation and the residue taken up in ethyl acetate andwashed with water, brine. Concentration and application to a 25 MBiotage cartridge, gradient elution with 10%-100% ethyl acetate/CH₂Cl₂,gave J11.a 90 mg (8.5%) and recovered starting material J9 696 mg (63%).

Example J32.a (S)-tert-butyl2-(5-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

3-(4-bromophenyl)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one(2.0 g, 6.2 mmol) was suspended in 5N sulfuric acid (60 mL) and heatedat 45° C. for 6 h. The temperature was raised to 85° C. for 2 h, andupon cooling a precipitate formed. This material which was isolated byfiltration to give 1-(4-bromophenyl)-3,3,3-trifluoropropane-1,2-dione1.6 g (92%) as a yellow solid. The dione (1.6 g, 5.7 mmol) was taken upin methanol (30 mL), N-(tert-butoxycarbonyl)-L-prolinal (1 g, 5.0 mmol)was added, followed by addition of 28% ammonium hydroxide solution (10mL). The reaction was stirred at room temperature for 18 h, poured ontodichloromethane (200 mL), washed with water and dried with MgSO₄.Filtration, concentration and application to a 40 M Biotage cartridge,gradient elution with 5%-30% ethyl acetate/Hexanes, gave J32.a 1.3 g(50%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.88 (br.s, 1H), 7.72 (d, J=8.4 Hz,2H), 7.39 (d, J=8.0 Hz, 2H), 4.84-4.70 (m, 1H), 3.57-3.49 (m, 1H),3.39-3.29 (m, 1H), 2.31-2.20 (m, 1H), 1.98-1.78 (m, 3H), 1.39/1.13 (m,9H). LRMS: Anal. Calcd. for C₁₉H₂₀BrF₃N₃O₂ 458.07. found: 458.06 and460.06 (M−H)⁻. HRMS: Anal. Calcd. for C₁₉H₂₂BrF₃N₃O₂ 460.0847. found:460.0866 and 462.0840 (M+H)⁺.

Section D Entry Compound Name Structure **Data D1

t_(R) = 2.65 min, (86.7%) LCMS: Anal Calcd. for C₈H₁₅BrFO 296.88; found:296.91 (M + H)⁺. D2

t_(R) = 2.66 min, (80%) LCMS: Anal. Calcd. for C₈H₄BrClFO 270.92; found:ND (M + H)⁺. D3

t_(R) = 2.57 min, (95%) LCMS: Anal. Calcd. for C₉H₉BrO₂ 228.99; found:229.00 (M + H)⁺. D4

t_(R) = 2.38 min, (95.0%) LRMS: Anal. Calcd. for C₁₉H₂₀ ⁷⁹BrFN₃O₂444.07; found: 444.04 (M + H)⁺. HRMS: Anal. Calcd. for C₁₉H₂₀ ⁷⁹BrFN₃O₂444.0721; found: 444.0736 (M + H)⁺ D5

t_(R) = 2.27 min, (95%) LRMS: Anal. Calcd. for C₁₈H₂₂BrFN₃O₂ 410.09 and412.08; found: 410.08 and 412.08 (M + H)⁺. HRMS: Anal. Calcd. for C₁₈H₂₂⁷⁹BrFN₃O₂ 410.0879; found: 410.0893 (M + H)⁺. D6

t_(R) = 2.26 min, (95%) LRMS: Anal. Calcd. for C₁₉H₂₅BrN₃O₃ 422.11 and424.11; found: 422.10 and 424.10 (M + H)⁺. HRMS: Anal. Calcd. for C₁₉H₂₅⁷⁹BrN₃O₃ 422.1079; found: 422.1089 (M + H)⁺. D7

t_(R) = 2.28 min, (95%) LRMS: Anal. Calcd. for C₁₈H₂₁ClF₂N₃O₂ 384.13;found: 384.13 (M + H)⁺. HRMS: Anal. Calcd. for C₁₈H₂₁ClF₂N₃O₂ 384.1290;found: 384.1301 (M + H)⁺. D8

t_(R) = 2.62 min, (~50%) and 1.95 min (~50%, boronic acid) LRMS: Anal.Calcd. for C₂₄H₃₄BFN₃O₄ 458.26; found: 458.23 (M + H)⁺. HRMS: Anal.Calcd. for C₂₄H₃₄BFN₃O₄ 458.2626; found: 458.2610 (M + H)⁺. D9tert-butyl (2S)-2-(4- (4′-(2-((2S)-1-(tert- butoxycarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- methoxy-3- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidine- carboxylate

t_(R) = 2.28 min, (95%) LRMS: Anal. Calcd. for C₃₇H₄₇N₆O₅ 655.36; found:655.37 (M + H)⁺. HRMS: Anal. Calcd. for C₃₇H₄₇N₆O₅ 655.3608; found:655.3627 (M + H)⁺. D10 di-tert-butyl (2S,2′S)- 2,2′-((3-fluoro-4,4′-biphenyl- diyl)bis(1H- imidazole-4,2- diyl))di(1-pyrrolidinecarboxylate)

t_(R) = 2.21 min, (99.2%) LCMS: Anal. Calcd. for C₃₆H₄₄FN₆O₄ 643.34;found: 643.51 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₄FN₆O₄ 643.3403;found: 643.3390 (M + H)⁺. D11 tert-butyl (2S)-2-(4-(4′-(2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2,5- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinecarboxylate

t_(R) = 2.24 min, (95%) LRMS: Anal. Calcd. for C₃₆H₄₃F₂N₆O₄ 661.33;found: 661.35 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₃F₂N₆O₄ 661.3314;found: 661.3336 (M + H)⁺. D12 di-tert-butyl (2S,2′S)-2,2′-((3,3′-difluoro- 4,4′- biphenyldiyl)bis(1H- imidazole-5,2-diyl)di(1- pyrrolidinecarboxylate)

t_(R) = 2.20 min, (95%) LRMS: Anal. Calcd. for C₃₆H₄₃F₂N₆O₄ 661.33;found: 661.22 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₃F₂N₆O₄ 661.3314;found: 661.3307 (M + H)⁺. D13 tert-butyl (2S)-2-(5-(2-(4-(2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-3- fluorophenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1-pyrrolidinecarboxylate

t_(R) = 2.27 min, (95%) LRMS: Anal. Calcd. for C₃₄H₄₂FN₈O₄ 645.33;found: 645.34 (M + H)⁺. HRMS: Anal. Calcd. for C₃₄H₄₂FN₈O₄ 645.3313;found: 645.3323 (M + H)⁺. D14 tert-butyl (2S)-2-(4- (4′-(2-((2S)-1-((benzyloxy)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-3-fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 2.26 min, (95%) LRMS: Anal. Calcd. for C₃₉H₄₂FN₆O₄ 677.33;found: 677.33 (M + H)⁺. HRMS: Anal. Calcd. for C₃₉H₄₂FN₆O₄ 677.3252;found: 677.3278 (M + H)⁺. D15 tert-butyl (2S)-2-(4- (4′-(2-((2S)-1-((benzyloxy)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-3,3′-difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 2.36 min, (97.3%) LRMS: Anal. Calcd. for C₃₉H₄₁F₂N₆O₄ 695.32;found: 695.33 (M + H)⁺. HRMS: Anal. Calcd. for C₃₉H₄₁F₂N₆O₄ 695.3157;found: 695.3151 (M + H)⁺. D16 tert-butyl (2S)-2-(5-(3-fluoro-4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidaozl-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 2.16 min, (91.0%) LRMS: Anal. Calcd. for C₄₁H₄₅FN₇O₅ 734.35;found: 734.36 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₅FN₇O₅ 734.3466;found: 734.3474 (M + H)⁺. D17 tert-butyl (2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 1.95 min, (95%) LRMS: Anal Calcd. for C₄₃H₅₁FN₇O₃ 732.40; found:732.44 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₅₁FN₇O₃ 732.4037; found:732.4065 (M + H)⁺. D18 tert-butyl (2S)-2-(5- (3-fluoro-4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 2.14 min, (95%) LRMS: Anal. Calcd. for C₃₈H₄₇FN₇O₅ 700.36;found: 700.37 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₇FN₇O₅ 700.3623;found: 700.3596 (M + H)⁺. D19 tert-butyl (2S)-2-(5-(3,3′-difluoro-4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidaozl-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 2.23 min, (95%) LRMS: Anal. Calcd. for C₄₁H₄₄F₂N₇O₅ 752.34;found: 752.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₄F₂N₇O₅ 752.3372;found: 752.3385 (M + H)⁺. D20 tert-butyl (2S)-2-(5-(3,3′-difluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinecarboxylate

t_(R) = 2.16 min, (90%) LRMS: Anal. Calcd. for C₃₈H₄₆F₂N₇O₅ 718.35;found: 718.36 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₆F₂N₇O₅ 718.3528;found: 718.3505 (M + H)⁺. D21 tert-butyl (2S)-2-(5-(3-fluoro-4′-(2-((2S)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate triacetate

t_(R) = 1.94 min, (95%) LRMS: Anal. Calcd. for C₃₁N₃₆FN₆O₂ 543.29;found: 543.30. HRMS: Anal. Calcd. for C₃₁H₃₆FN₆O₂ 543.2884; found:543.2872 (M + H)⁺. D22 tert-butyl (2S)-2-(5- (3,3′-difluoro-4′-(2-((2S)-2-pyrrolidinyl)- 1H-imidaozl-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinecarboxylate

t_(R) = 2.14 min, (95%) LRMS: Anal. Calcd. for C₃₁H₃₅F₂N₆O₂ 561.28;found: 561.29 (M + H)⁺. HRMS: Anal. Calcd. for C₃₁H₃₅F₂N₆O₂ 561.2790;found: 561.2766 (M + H)⁺. D23 methyl ((1R)-2-((2S)-2-(5-(3′-fluoro-4′-(2- ((2S)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 1.90 min, (94%) LRMS: Anal. Calcd. for C₃₆H₃₇FN₇O₃ 634.29;found: 634.29 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₃₇FN₇O₃ 634.2942;found: 634.2948 (M + H)⁺. D24 methyl ((1S)-1- (((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.89 min, (95%) LRMS: Anal. Calcd. for for C₃₃H₃₉FN₇O₃ 600.31;found: 600.32 (M + H)⁺. HRMS: Anal. Calcd. for C₃₃H₃₉FN₇O₃ 600.3098;found; 600.3121 (M + H)⁺. D25 (1R)-N,N-diethyl-2- ((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethanamine

t_(R) = 1.72 min, (90%) LRMS: Anal. Calcd. for C₃₈H₄₃FN₇O 632.35; found:632.36 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₃FN₇O 632.3513; found:632.3527 (M + H)⁺. D26 methyl ((1S)-1- (((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carba- mate

t_(R) = 1.96 min, (95%) LRMS: Anal. Calcd. for C₃₃H₃₈F₂N₇O₃ 618.30;found: 618.31 (M + H)⁺. HRMS: Anal. Calcd. for C₃₃H₃₈F₂N₇O₃ 618.3004;found: 618.3024 (M + H)⁺. D27 methyl ((1R)-2-((2S)-2-(5-(3,3′-difluoro-4′- (2-((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 1.63 min, (95%) LRMS: Anal. Calcd. for C₃₆H₃₆F₂N₇O₃ 652.28;found: 652.29 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₃₆F₂N₇O₃ 652.2848;found: 652.2858 (M + H)⁺. D28 5,5′-(4-methoxy-3,4′- biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)- 1H-imidazole)

t_(R) = 1.53 min, (98.2%) LRMS: Anal. Calcd. for C₂₇H₃₁N₆O 455.26;found: 455.26 (M + H)⁺. HRMS: Anal. Calcd. for C₂₇H₃₁N₆O 455.2559;found: 455.2576 (M + H)⁺. D29 5,5′-(3-fluoro-4,4′- biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)- 1H-imidazole) tetraacetate

t_(R) = 1.55 min, (95%) LRMS: Anal. Calcd. for C₂₆H₂₈FN₆ 443.24; found:443.24 (M + H)⁺. HRMS: Anal. Calcd. for C₂₆H₂₈FN₆ 443.2359; found:443.2371 (M + H)⁺. D30

t_(R) = 1.72 min, (77.5%) LRMS: Anal. Calcd. for C₂₆H₂₇F₂N₆ 461.23;found: 461.25 (M + H)⁺. HRMS: Anal. Calcd. for C₂₆H₂₇F₂N₆ 461.2265;found: 461.2272 (M + H)⁺. D31 5,5′-(2,5-difluoro- 4,4′-biphenyldiyl)bis(2- ((2S)-2-pyrrolidinyl)- 1H-imidazole)

t_(R) = 1.67 min, (95%) LRMS: Anal. Calcd. for C₂₆H₂₇F₂N₆ 461.23; found:461.23 (M + H)⁺. HRMS: Anal. Calcd. for C₂₆H₂₇F₂N₆ 461.2265; found:461.2287 (M + H)⁺. D32 2-(3-fluoro-4-(2- ((2S)-2-pyrrolidinyl)-1H-imidazol-5- yl)phenyl)-5-(2-((2S)- 2-pyrrolidinyl)-1H- imidazol-5-yl)pyrimidine

t_(R) = 1.63 min, (95%) LRMS: Anal. Calcd. for C₂₄H₂₆FN₈ 445.23; found:445.23 (M + H)⁺. HRMS: Anal. Calcd. for C₂₄H₂₆FN₈ 445.2264; found:445.2268 (M + H)⁺. D33 (1R,1′R)-2,2′-((4- methoxy-3,4′-biphenyldiyl)bis(1H- imidaozle-5,2- diyl(2S)-2,1-pyrrolidinediyl))bis(N,N- dimethyl-2-oxo-1- phenylethanamine)

t_(R) = 1.71 min, (95%) LRMS: Anal. Calcd. for C₄₇H₅₃N₈O₃ 777.42; found:777.41 (M + H)⁺. HRMS: Anal. Calcd. for C₄₇H₅₃N₈O₃ 777.4241; found:777.4254 (M + H)⁺. D34 dimethyl ((4- methoxy-3,4′- biphenyldiyl)bis(1H-imidaozle-5,2- diyl(2S)-2,1- pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1-ethanediyl)))biscarba- mate

t_(R) = 2.09 min, (95%) LRMS: Anal. Calcd. for C₄₇H₄₉N₈O₇ 837.37; found:837.34 (M + H)⁺. HRMS: Anal. Calcd. for C₄₇H₄₉N₈O₇ 837.3724; found:837.3690 (M + H)⁺. D35 methyl ((1S)-1- (((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.85 min, (97.2%) LRMS: Anal. Calcd. for C₄₅H₅₄FN₈O₄ 789.43;found: 789.43 (M + H)⁺. HRMS: Anal. Calcd. for C₄₅H₅₄FN₈O₄ 789.4252;found: 789.4225 (M + H)⁺. D36 methyl ((1S)-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.76 min, (97.9%) LRMS: Anal. Calcd. for C₄₃H₅₀FN₈O₄ 761.39;found: 761.26 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₅₀FN₈O₄ 761.3939;found: 761.3967 (M + H)⁺. D37 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.90 min, (98.6%) LRMS: Anal. Calcd. for C₄₈H₅₂FN₈O₄ 823.41;found: 823.42 (M + H)⁺. HRMS: Anal. Calcd. for C₄₈H₅₂FN₈O₄ 823.4096;found: 823.4102 (M + H)⁺. D38 methyl ((1R)-2-((2S)-2-(5-(3′-fluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-1- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.89 min, (98.2%) LRMS: Anal. Calcd. for C₄₇H₄₉N₈O₇ 763.34;found: 763.32 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₄FN₈O₆ 763.3368;found: 763.3358 (M + H)⁺. D39 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.88 min, (98.7%) LRMS: Anal. Calcd. for C₄₈H₅₂FN₈O₄ 823.41;found: 823.39 (M + H)⁺. HRMS: Anal. Calcd. for C₄₈H₅₂FN₈O₄ 823.4096;found: 823.4127 (M + H)⁺. D40 methyl ((1S)-1- (((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)- amino)-3- methylbutanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.97 min, (98.4%) LRMS: Anal. Calcd. for C₄₀H₅₀FN₈O₆ 757.38;found: 757.32 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₅₀FN₈O₆ 757.3837;found: 757.3815 (M + H)⁺. D41 methyl ((1S)-1- (((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.82 min, (95.0%) LRMS: Anal. Calcd. for C₃₈H₄₆FN₈O₆ 729.35;found: 729.29 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₆FN₈O₆ 729.3524;found: 729.3523 (M + H)⁺. D42 methyl ((1S,2R)-1- (((2S)-2-(5-(3-fluoro-4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methoxypropyl)carba- mate

t_(R) = 1.91 min, (94.0%) LRMS: Anal. Calcd. for C₄₀H₅₀FN₈O₇ 773.38;found: 773.31 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₅₀FN₈O₇ 773.3786;found: 773.3759 (M + H)⁺. D43 methyl ((1S)-1- (((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl- D-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′-fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2-methylpropyl)carba- mate

t_(R) = 1.72 min, (97.6%) LRMS: Anal. Calcd. for C₄₀H₅₂FN₈O₄ 727.41;found: 727.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₅₂FN₈O₄ 727.4096;found: 727.4091 (M + H)⁺. D44 methyl ((1S)-1- (((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.83 min, (96.9%) LRMS: Anal. Calcd. for C₄₅H₅₄FN₈O₄ 789.43;found: 789.36 (M + H)⁺. HRMS: Anal. Calcd. for C₄₅H₅₄FN₈O₄ 789.4252;found: 789.4225 (M + H)⁺. D45 methyl ((1S)-2-((2S)-2-(5-(3′-fluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.69 min, (97.7%) LRMS: Anal. Calcd. for for C₃₆H₄₂FN₈O₆ 701.32;found: 701.30 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₂FN₈O₆ 701.3222;found: 701.3211 (M + H)⁺. D46 dimethyl ((3-fluoro- 4,4′-biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarba- mate

t_(R) = 2.05 min, (99.9%) LRMS: Anal. Calcd. for for C₄₆H₄₆FN₈O₆ 825.35;found: 825.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₆H₄₆FN₈O₆ 825.3524;found: 825.3522 (M + H)⁺. D47 (1R,1′R)-2,2′-((3- fluoro-4,4′-biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis-(N,N-diethyl-2-oxo-1- phenylethanamine)

t_(R) = 1.72 min, (99.5%) LRMS: Anal. Calcd. for for C₅₀H₅₈FN₈O₂ 821.47;found: 821.44 (M + H)⁺. HRMS: Anal. Calcd. for C₅₀H₅₈FN₈O₂ 821.4667;found: 821.4636 (M + H)⁺. D48 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D- alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′-fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 1.76 min, (99.7%) LRMS: Anal. Calcd. for C₄₃H₅₀FN₈O₄ 761.39;found: 761.27 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₅₀FN₈O₄ 761.3939;found: 761.3952 (M + H)⁺. D49 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate

t_(R) = 1.92 min, (98.7%) LRMS: Anal. Calcd. for C₄₅H₅₂FN₈O₄ 787.41;found: 787.36 (M + H)⁺. HRMS: Anal. Calcd. for C₄₅H₅₂FN₈O₄ 787.4096;found: 787.4074 (M + H)⁺. D50 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(3-fluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

t_(R) = 1.94 min, (99.0%) LRMS: Anal. Calcd. for C₄₀H₄₈F₂N₈O₇ 755.37;found: 755.32 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₈FN₈O₆ 755.3681;found: 755.3670 (M + H)⁺. D51 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D- alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′-fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 1.92 min, (98.3%) LRMS: Anal. Calcd. for C₄₃H₅₀FN₈O₄ 761.39;found: 761.35 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₅₀FN₈O₄ 761.3939;found: 761.3956 (M + H)⁺. D52 methyl ((1S)-2-((2S)-2-(5-(2′,5′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.69 min, (99.2%) LRMS: Anal. Calcd. for C₃₆H₄₁F₂N₈O₆ 719.31;found: 719.29 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₁F₂N₈O₆ 719.3117;found: 719.3109 (M + H)⁺. D53 dimethyl ((2,5- difluoro-4,4′-biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarba- mate

t_(R) = 2.08 min, (100.0%) LRMS: Anal. Calcd. for C₄₆H₄₅F₂N₈O₆ 843.34;found: 843.34 (M + H)⁺. HRMS: Anal. Calcd. for C₄₆H₄₅F₂N₈O₆ 843.3430;found: 843.3458 (M + H)⁺. D54 (1R,1′R)-2,2′-((2,5- difluoro-4,4′-biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis-(N,N-diethyl-2-oxo-1- phenylethanamine)

t_(R) = 1.76 min, (99.8%) LRMS: Anal. Calcd. for C₅₀H₅₇F₂N₈O₂ 839.46;found: 839.43 (M + H)⁺. HRMS: Anal. Calcd. for C₅₀H₅₇F₂N₈O₂ 839.4573;found: 839.4585 (M + H)⁺. D55 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(3,3′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

t_(R) = 1.93 min, (98.5%) LRMS: Anal. Calcd. for C₄₀H₄₇F₂N₈O₆ 773.36;found: 773.31 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₇F₂N₈O₆ 773.3567;found: 773.3587 (M + H)⁺. D56 methyl ((1S,2R)-1- (((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)- 1-(N- (methoxycarbonyl)- L-valyl)-2-pyrroldinyl)-1H- imidaozl-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methoxypropyl)carba- mate

t_(R) = 2.00 min, (98.0%) LRMS: Anal. Calcd. for C₄₀H₄₉F₂N₈O₇ 791.37;found: 791.32 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₉F₂N₈O₇ 791.3692;found: 791.3682 (M + H)⁺. D57 methyl ((1S)-1- (((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)- 1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.86 min, (95.6%) LRMS: Anal. Calcd. for C₃₈H₄₅F₂N₈O₆ 747.34;found: 747.30 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₅F₂N₈O₆ 747.3430;found: 747.3425 (M + H)⁺. D58 methyl ((1S)-1- (((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)- 1-((2S)-2- ((methoxycarbonyl)- amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2- methylpropyl)carbamate

t_(R) = 2.02 min, (96.3%) LRMS: Anal. Calcd. for C₄₀H₄₉F₂N₈O₆ 775.37;found: 775.31 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₄₉F₂N₈O₆ 775.3743;found: 775.37.34 (M + H)⁺. D59 methyl ((1S)-1- (((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl- D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3,3′- difluoro-4- biphenylyl)-1H- imidaozl-2-yl)-1-pyrrolidinyl)carbonyl)- 2- methylpropyl)carba- mate

t_(R) = 1.78 min, (98.2%) LRMS: Anal. Calcd. for C₄₀H₅₁F₂N₈O₄ 745.40;found: 745.34 (M + H)⁺. HRMS: Anal. Calcd. for C₄₀H₅₁F₂N₈O₄ 745.4001;found: 745.4008 (M + H)⁺. D60 methyl ((1S)-1- (((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2- methylpropyl)carbamate

t_(R) = 2.08 min, (99.1%) LRMS: Anal. Calcd. for C₄₃H₄₇F₂N₈O₆ 809.36;found: 809.29 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₄₇F₂N₈O₆ 809.3587;found: 809.3568 (M + H)⁺. D61 methyl ((1S)-2-((2S)-2-(5-(3,3′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.71 min, (94.3%) LRMS: Anal. Calcd. for C₃₆H₄₁F₂N₈O₆ 719.31;found: 719.19 (M + H)⁺. HRMS: Anal. Calcd. for C₃₆H₄₁F₂N₈O₆ 719.3117;found: 719.3115 (M + H)⁺. D62 methyl ((1R)-2-((2S)-2-(5-(3,3′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.94 min, (98.3%) LRMS: Anal. Calcd. for C₄₁H₄₃F₂N₈O₆ 781.33;found: 781.26 (M + H)⁺. HRMS: Anal. Calcd. for C₄₁H₄₃F₂N₈O₆ 781.3274;found: 781.3264 (M + H)⁺. D63 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D- alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3,3′-difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 1.44 min, (99.0%) LRMS: Anal. Calcd. for C₄₃H₄₉F₂N₈O₄ 779.38;found: 779.32 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₄₉F₂N₈O₄ 779.3845;found: 779.3842 (M + H)⁺. D64 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-3,3′- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo- 1- phenylethyl)carbamate

t_(R) = 1.94 min, (95.3%) LRMS: Anal. Calcd. for C₄₈H₅₁F₂N₈O₄ 841.40;found: 841.33 (M + H)⁺. HRMS: Anal. Calcd. for C₄₈H₅₁F₂N₈O₄ 841.4001;found: 841.3991 (M + H)⁺. D65 methyl ((1S,2R)-1- (((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl)- amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methoxypropyl)carbamatebis(trifluoroacetate)

t_(R) = 2.00 min, (96.2%) LRMS: Anal. Calcd. for C₄₃H₄₇F₂N₈O₇ 825.35;found: 825.28 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₄₇F₂N₈O₇ 825.3536;found: 825.3527 (M + H)⁺. D66 methyl ((1S)-1- cyclopropyl-2-((2S)-2-(5-(3,3′-difluoro-4′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl)-amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate

t_(R) = 2.01 min, (99.5%) LRMS: Anal. Calcd. for C₄₃H₄₅F₂N₈O₆ 807.34;found: 807.29 (M + H)⁺. HRMS: Anal. Calcd. for C₄₃H₄₅F₂N₈O₆ 807.3430;found: 807.3409 (M + H)⁺. D67 methyl ((1S)-2-((2S)- 2-(5-(2-fluoro-4-(5-(2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

t_(R) = 1.58 min, (91.1%) LRMS: Anal. Calcd. for C₃₄H₄₀FN₁₀O₆ 703.31;found: 703.27 (M + H)⁺. HRMS: Anal. Calcd. for C₃₄H₄₀FN₁₀O₆ 703.3116;found: 703.3101 (M + H)⁺. D68 methyl ((1S)-1- (((2S)-2-(5-(2-fluoro-4-(5-(2-((2S)-1-((2S)- 2-((methoxycarbonyl)- amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-pyrimidinyl)phenyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

t_(R) = 1.95 min, (99.3%) LRMS: Anal. Calcd. for C₃₈H₄₈FN₁₀O₆ 759.37;found: 759.30 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₈FN₁₀O₆ 759.3742;found: 759.3715 (M + H)⁺. D69 methyl ((1R)-2-((2S)- 2-(5-(2-(3-fluoro-4-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)- amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate

t_(R) = 2.05 min, (99.3%) LRMS: Anal. Calcd. for C₄₄H₄₄FN₁₀O₆ 827.34;found: 827.27 (M + H)⁺. HRMS: Anal. Calcd. for C₄₄H₄₄FN₁₀O₆ 827.3429;found: 827.3407 (M + H)⁺. D70 methyl ((1S,2R)-1- (((2S)-2-(5-(2-fluoro-4-(5-(2-((2S)-1-(N- (methoxycarbonyl)- O-methyl-L- threonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2- methoxypropyl)carba-mate

t_(R) = 1.79 min, (93.0%) LRMS: Anal. Calcd. for C₃₈H₄₈FN₁₀O₈ 791.36;found: 791.31 (M + H)⁺. HRMS: Anal. Calcd. for C₃₈H₄₅FN₁₀O₈ 791.3641;found: 791.3636 (M + H)⁺. **LCMS conditions: Phenomenex-Luna 4.6 × 50 mmS10, 0 to 100% B over 3 min, 4 min stop time, 4 mL/min, 220 nm, A: 10%MeOH-90% H2O - 0.1% TFA; B: 90% MeOH-10% H2O-0.1% TFA

Example D5 (S)-tert-butyl2-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Bromine (0.54 mL, 10.6 mmol) was added dropwise to a cold (0° C.)solution of 4-bromo-2-fluoroacetophenone (2.30 g, 10.6 mmol) in dioxane(80 mL) and tetrahydrofuran (80 mL). The mixture was stirred for 1 h at0° C. and warmed to RT for 15 h. The mixture was diluted with ethylacetate, washed with saturated NaHCO₃ solution, 5% sodium thiosulfatesolution and brine prior to drying (Na₂SO₄).2-Bromo-1-(4-bromo-2-fluorophenyl)ethanone (D1) was isolated as acolorless film which solidified upon further concentration under highvacuum. This solid was dissolved into anhydrous acetonitrile (50 mL) andtreated with N-Boc-L-proline (2.28 g, 10.6 mmol) anddiisopropylethylamine (1.85 mL, 10.6 mmol). After being stirred for 3 hat RT, the solvent was removed in vacuo and the residue was partitionedinto ethyl acetate and water. The organic phase was washed with 0.1Nhydrochloric acid, saturated NaHCO₃ solution and brine prior to drying(Na₂SO₄), filtration, and concentration. This residue was taken up inxylenes (50 mL) and treated to solid NH₄OAc (4.1 g, 53.0 mmol). Themixture was heated at 140° C. for 2 hr in a thick-walled, screw-topflask before it was cooled to ambient temperature, diluted with ethylacetate and washed with saturated NaHCO₃ solution and brine prior todrying (Na₂SO₄) and concentration. Purification of the residue byBiotage™ flash chromatography on silica gel (65M column,preequilibration with 16% B for 1800 mL followed by gradient elutionwith 16% B to 16% B for 450 mL, 16% B to 50% B for 2199 ml and finally50% B to 100% B for 2199 mL) afforded title compound (D5) (3.61 g, 83%)as a brownish/caramel-colored oil. A small portion (40 mg) of the titlecompound was further purified by preparative HPLC (20% B to 100% B over14 min where B is 10 mM NH₄OAc in 10:90 H₂O/ACN and A is 10 mM NH₄OAc in95:5 H₂O/CAN using a Phenomenex-Gemini 30×100 mm S10 column flowing at40 mL/min) to afford pure title compound (31.8 mg) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 12.13-11.95 (m, 1H), 7.94 (br s, 1H), 7.54(d, J=10.7 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.34 (m, 1H), 4.86-4.77(2m, 1H), 3.54 (m, 1H), 3.38-3.32 (m, 1H), 2.28-2.14 (2m, 1H), 2.05-1.78(2m, 3H), 1.39 and 1.14 (2s, 9H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=2.27 min, 95% homogeneity index.

LRMS: Anal. Calcd. for C₁₈H₂₂BrFN₃O₂ 410.09 and 412.09. found: 410.08and 412.08 (M+H)⁺.

HRMS: Anal. Calcd. for C₁₈H₂₂BrFN₃O₂ 410.0879. found: 410.0893 (M+H)⁺.

Examples M1-M27

Example M1-M27 were prepared from 1e and the respective acids using themethod described for Example 1. The products were prepared as TFA salts,unless noted otherwise. LC Conditions were as follows:

Condition 1

Column=Phenomenex-Luna 3.0×50 mm S10

Start % B=0

Final % B=100

Gradient time=2 min

Stop time=3 min

Flow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition 2

Column=Phenomenex-Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient time=2 min

Stop time=3 min

Flow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition 3

Column=HPLC XTERRA C18 3.0×50 mm S7

Start % B=0

Final % B=100

Gradient time=3 min

Stop time=4 min

Flow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂O

Solvent B=0.1% TFA in 90% methanol/10% H₂O

Condition M1

Column: Luna 4.6×50 mm S10

Start % B=0

Final % B=100

Gradient time=3 min

Stop time=4 min

Flow rate=4 mL/min

Solvent A:=95% H₂O: 5% CH₃CN, 10 mm Ammonium acetate

Solvent B:=5% H₂O: 95% CH₃CN; 10 mm Ammonium acetate

Example Compound Name

RT (LC-Cond.); % homogeneity index; MS data; ¹H NMR data M1 7,7′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl(2-oxo-1-phenyl-2,1- ethanediyl)))bis(7- azabicyclo[2.2.1]heptane)

1.04 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₅₄H₅₉N₈O₂:851.48; found 851.55; HRMS: Anal. Calcd. for [M + H]⁺ C₅₄H₅₉N₈O₂:851.4761; found 851.4780 M2 7,7′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl(2-oxo-1- phenyl-2,1-ethanediyl)))bis(7- azabicyclo[2.2.1]heptane)

1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₅₄H₅₉N₈O₂:851.48; found 851.57; HRMS: Anal. Calcd. for [M + H]⁺ C₅₄H₅₉N₈O₂:851.4761; found 851.4792 M3 N,N′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo- 1-phenyl-2,1-ethanediyl)))bis(N- ethylcyclopropanamine)

1.13 min (Cond. 1); >95%; LC/MS: Anal. Calcd. for [M + H]⁺ C₅₂H₅₉N₈O₂:827.48; found 827.69; HRMS: Anal. Calcd. for [M + H]⁺ C₅₂H₅₉N₈O₂:827.4761; found 827.4782 M4 ethyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N-(ethoxycarbonyl)-D-alanyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

1.20 min (Cond. 1); >97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.36; found 711.46; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.3619; found 711.3638 M5 ethyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N-(ethoxycarbonyl)-L-alanyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

1.16 min (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.36; found 711.48; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.3619; found 711.3621 M6 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediylcarbonyl-1,1-cyclopropanediyl)) biscarbamate

1.12 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₃N₈O₆:707.33; found 707.45; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₃N₈O₆:707.3306; found 707.3309 M7 methyl (2-((2S)-2-(5-(4′-(2- ((2S)-1-(2-((methoxycarbonyl)amino)- 2-methylpropanoyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1,1-dimethyl- 2-oxoethyl)carbamate

1.21 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.36; found 711.53; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.3619; found 711.3652 M8 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- dimethyl-1-oxo-2-propanamine)

0.91 min (Cond. 1); >80%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₇N₈O₂:623.38; found 623.46; HRMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₇N₈O₂:623.3822; found 623.3819 M9 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- diethyl-1-oxo-2-propanamine)

1.00 min (Cond. 1); >95%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₅N₈O₂:623.38; found 679.67; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₅N₈O₂:679.4448; found 679.4432 M10 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N-diethyl-3-methyl-1-oxo-2- butanamine)

1.03 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₆₃N₈O₂:735.51; found 735.76; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₆₃N₈O₂:735.5074; found 735.5060 M11 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)(methyl)amino)-3-methylbutanoyl)- 2-pyrrolidinyl)1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl) methylcarbamate

1.46 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₅N₈O₂:767.42; found 767.38; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₅N₈O₂:767.4245; found 767.4252 M12 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1S)-2-oxo- 1-phenyl-2,1-ethanediyl)))biscarbamate

1.32 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₆:807.36; found 807.32; HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₆:807.3619; found 807.3651 M13 N,N′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((2R)-1-oxo-1,2-propanediyl)))bis(N- propyl-1-propanamine)

1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₆₃N₈O₂:735.51; found 735.46; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₆₃N₈O₂:735.5074; found 735.5063 M14 methyl ((1S)-2-hydroxy-1-(((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-3-hydroxy-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₈:771.38; found 771.21 M15 methyl ((1S,2R)-2-hydroxy-1-(((2S)-2-(5-(4′-(2-((2S)-1- ((2S,3R)-3-hydroxy-2-((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)propyl)carbamate

1.10 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₈:743.35; found 753.23; ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz), ~14.5 (brs, 4 H), 8.15 (s, 2 H), 7.97 (d, J = 8.5, 4 H), 7.89 (d, J = 8.4, 4 H),7.10/7.05 (two overlapping d, J = 8.0, 8.4, 1.82 H), 6.57 (app br s,0.18 H), 5.78 (br d, J = 7.9, 0.18 H), 5.16 (m, 1.82 H), 4.27 (dd, J =8.0, 5.3, 1.82 H), 4.10 (m, 0.18 H), 3.96-3.81 (m, 6 H), 3.55 (s, 5.46H), 3.37 (s, 0.54 H), 2.41 (m, 2 H), 2.17-2.00 (m, 6 H), 1.10 (d, J =6.3, 0.54 H), 1.04 (d, J = 6.3, 5.46 H). M16 methyl ((1S,2S)-2-hydroxy-1-(((2S)-2-(5-(4′-(2-((2S)-1- ((2S,3S)-3-hydroxy-2-((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)carbonyl)propyl)carbamate

1.11 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₈:743.35; found 743.23 M17 methyl ((1S)-2-((2S)-2-(5- (4′-(2-((2S)-1-(N-(methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

1.64 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₃N₈O₆:683.33; found 683.30; HRMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₃N₈O₆:683.3306; found 683.3305. M18 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-D- alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.70 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₃N₈O₆:683.33; found 683.32; HRMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₃N₈O₆:683.3306; found 683.3318. M19 (2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl)bis(N,N- dimethyl-1-oxo-2-propanamine)

1.43 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₇N₈O₂:623.38; found 623.43; HRMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₇N₈O₂:623.3822; found 623.3837. M20 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((2R)-1-oxo- 1,2-butanediyl))biscarbamate

1.82 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.36; found 711.35; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.3619; found 711.3649. M21 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((2S)-1-oxo- 1,2-butanediyl))biscarbamate

1.81 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.36; found 711.35; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆:711.3619; found 711.3643. M22 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-1-cyclopropyl-2-oxo-2,1- ethandiyl)))biscarbamate

1.83 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₇N₈O₆:735.36; found 735.44; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₇N₈O₆:735.3619; found: 735.3614. M23 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1S)-1-cyclopropyl-2-oxo-2,1- ethandiyl)))biscarbamate

1.81 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₇N₈O₆:735.36; found 735.43; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₇N₈O₆:735.3619; found 735.3651. M24 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2,2-dimethylpropyl)carbamate

2.11 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₅N₈O₆:767.42; found 767.58; HRMS: Anal. Calcd. for C₄₂H₅₅N₈O₆: 767.4245; found767.4230. M25 dimethyl (4,4′- biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((4S)-5-oxo- 1-penten-5,4-diyl)))biscarbamate

1.91 min (Cond. 2); 98% LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₇N₈O₆:735.36; found 735.47; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₇N₈O₆:735.3619; found 735.3630. M26 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-O- methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- (methoxymethyl)-2- oxoethyl)carbamate

1.72 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₈:743.35; found 743.49; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₈:743.3517; found 743.3489. M27 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)pentanoyl)-2-pyrrolidinyl)- 1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)butyl) carbamate

1.98 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₆:736.39; found 739.52; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₆:739.3932; found 739.3904.

Example M28 methyl((1S)-1-(((2R)-2-(5-(4′-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M28 Step a

Bromide M28a was prepared from D-Proline according to the proceduredescribed for its enantiomer 28b.

Example M28 Step b

Boronate ester M28b was prepared from bromide M28a according to theprocedure described for intermediate 1c. LC: RT=1.57 min (Cond. 1);LC/MS: Anal. Calcd. for [M+H]⁺ C₂₇H₃₃BN₃O₄: 474.26. found 474.24.

Example M28 Step c

Biphenyl M28c was prepared from bromide M28a and boronate M28b accordingto the procedure described for intermediate 1d. LC: RT=1.43 min (Cond.1); LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₄₁N₆O₄: 693.32. found 693.38.

Example M28 Step d

Pyrrolidine M28d was prepared from carbamate M28c according to theprocedure described for intermediate 28d. ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz): δ 11.83 (br s, 2H), 7.80 (d, J=8.3, 4H), 7.66 (d, J=8.3, 4H),7.46 (br s, 2H), 4.16 (app t, J=7.2, 2H), 3.00-2.94 (m, 2H), 2.88-2.82(m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H). [Note:in the region between 3.2-2.6 ppm there is a broad base-line signal thatis believed to be that of the pyrrolidine NH]. LC: RT=1.02 min (Cond.1); LC/MS: Anal. Calcd. for [M+H]⁺ C₂₆H₂₉N₆: 425.25. found 425.27.

Example M28

Example M28 was prepared as TFA salt from intermediate M28d and Cap-51according to the procedure described for Example 1. LC: RT=1.33 min(Cond. 1); 96% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₀H₅₁N₈O₆: 739.32. found 739.43; HRMS: Anal. Calcd. for [M+H]⁺C₄₀H₅₁N₈O₆: 739.3932. found 739.3907.

Example M28-1

The TFA salt of Example M28-1 was prepared as a mixture of threestereoisomers from intermediate M28d and racemic version of Cap-51according to the procedure described for Example 1. Three peaks with aretention time of 21.74 min, 22.62 min, and 23.40 min, and exhibitingthe correct molecular weight, were observed when the sample was analyzedunder the following condition:

Waters Acquity HPLC with Micromass ZQ MS (electrospray probe) and Waters2996 PDA detection. (UV detection (315 nm)

Column: Acquity HPLC; BEH C18; 1.7 um; 100×2.1 mm ID; (at approx. 30 C)

Mobile phase A: water, 25 mM ammonium acetate at pH=5

Mobile phase B: acetonitrile

Flow rate: 0.50 ml/min

10-50% B 0-35.0 min

50-98% B 35.0-45.0 min

Hold 98% B 45.0-48.0 min

98% B-100% B 48.0-48.5 min

Hold 100% B 48.5-50.0 min

Example M28-2 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M28-2 Step a

Carbamate M28-2a was prepared from boronate ester M28b and bromide 28baccording to the procedure described for intermediate 1d. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.25/12.01/11.93 (three br s, 2H),7.86-6.98 (m, 20H), 5.13-4.88 (m, 6H), 3.63 (m, 2H), 3.47 (m, 2H),2.35-1.84 (M, 8H). LC: RT=1.46 min (Cond. 1); LC/MS: Anal. Calcd. for[M+H]⁺ C₄₂H₄₁N₆O₄: 693.32. found 693.34.

Example M28-2 Step b

Pyrrolidine M28-2b was prepared from carbamate M28-2a according to theprocedure described for intermediate 28d. ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz): δ 11.84 (br s, 2H), 7.80 (d, J=8.3, 4H), 7.66 (d, J=8.3, 4H),7.46 (br s, 2H), 4.87 (m, 0.05H), 4.16 (app t, J=7.2, 1.95H), 3.00-2.94(m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H),1.82-1.66 (m, 4H). [Note: in the region between ˜3.1-2.6 ppm there is abroad base-line signal that is believed to be that of the pyrrolidineNH]. LC: RT=0.96 min (Cond. 1); LC/MS: Anal. Calcd. for [M+H]⁺ C₂₆H₂₉N₆:425.25. found 425.28.

Example M28-2

Example M28-2 was prepared as TFA salt from intermediate M28-2b andCap-51 according to the procedure described for Example 1. LC: RT=1.96minutes (Cond. 2); 98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₀H₅₁N₈O₆ 739.39. found 739.47.

Example M28-3

The TFA salt of Example M28-3 was prepared as a mixture of fourstereoisomers from intermediate M28-2b and racemic version of Cap-51according to the procedure described for Example 1. Three peaks with aretention time of 21.28 min, 22.19 min, and 23.01 min, and exhibitingthe correct molecular weight, were observed when the sample was analyzedunder the LC/MS condition described for Example M28-1.

Example M29 dimethyl(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2R)-2,1-pyrrolidinediyl((1R)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate

Example M29 was prepared as TFA salt from intermediate M28d and Cap-54aaccording to the procedure described for Example 1. LC: RT=1.21 min(Cond. 1); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₀H₄₇N₈O₆: 735.36. found 735.42; HRMS: Anal. Calcd. for [M+H]⁺C₄₀H₄₇N₈O₆: 735.3619. found 735.3598.

Example M30-M62

Example M30-M62 were prepared as TFA salts from CJ-24 and the respectivecaps using the same method described for Example 28.

Example Compound Name

RT (LC-Cond.); % homogeneity index; MS data M30 ethyl((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.42; found 757.50; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.4190; found 757.4181 M31 ethyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

1.07 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.42; found 757.55; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.4190; found 757.4225 M32 (5S)-5-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- pyrrolidinone

1.02 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₉N₈O₃:725.39; found 725.48; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₉N₈O₃:725.3928; found 725.3926 M33 methyl (1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopropyl) carbamate

1.12 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₁N₈O₄:755.40; found 755.61; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₁N₈O₄:755.4033; found 755.4066 M34 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1,1-dimethyl-2- oxoethyl)carbamate

1.16 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.42; found 757.63; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.4190; found 757.4164 M35 (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-1-oxo-2- propanamine

1.06 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₇N₈O₂:741.46; found 741.64; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₇N₈O₂:741.4604; found 741.4597 M36 (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-1-oxo-2- propanamine

1.04 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₇N₈O₂:741.46; found 741.63; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₇N₈O₂:741.4604; found 741.4581 M37 (1R)-N,N-diethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-oxazol-2- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine

1.11 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₅N₈O₃:709.36; found 709.51; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₅N₈O₂:709.3615; found 709.3615 M38 (1R)-N,N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-(3-pyridinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₄₇N₈O₃:719.38; found 719.51; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₄₇N₈O₂:719.3822; found 719.3829 M39 (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-propanol

1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₈N₇O₃:686.38; found 686.58; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₈N₇O₃:686.3819; found 686.3843 M40 (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-propanol

1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₈N₇O₃:686.38; found 686.57; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₈N₇O₃:686.3819; found 686.3832 M41 methyl (1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclobutyl) carbamate

1.19 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.42; found 769.66; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.419; found 469.4155 M42 methyl (1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl) carbamate

1.25 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₅N₈O₄:783.43; found 783.69; HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₅N₈O₄:783.4346; found 783.4357 M43 N-((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-N-propyl-1- propanamine

1.10 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₇H₆₁N₈O₂:769.49; found 769.69; HRMS: Anal. Calcd. for [M + H]⁺ C₄₇H₆₁N₈O₂:769.4917; found 769.4925 M44 (4S)-4-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1,3- oxazolidin-2-one

1.08 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₇N₈O₄:727.37; found 727.56; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₇N₈O₄:727.3720; found 727.3740 M45 (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-3-methyl-1-oxo-2- butanamine

1.08 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₇H₆₁N₈O₂:769.49; found 769.73; HRMS: Anal. Calcd. for [M + H]⁺ C₄₇H₆₁N₈O₂:769.4917; found 769.4898 M46 N-((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-N-propyl-1- propanamine

1.12 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₇H₆₁N₈O₂:769.49; found 769.45; HRMS: Anal. Calcd. for [M + H]⁺ C₄₇H₆₁N₈O₂:769.4917; found 769.4915 M47 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.85 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₃N₈O₄:805.42; found 805.4; HRMS: Anal. Calcd. for [M + H]⁺: C₄₈H₅₃N₈O₄805.4190; found 805.4196. M48 (1R)-N,N-diethyl-2-(2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(4-morpholinyl)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine

1.69 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₅₀H₅₇N₈O₃:817.45; found 817.48; HRMS: Anal. Calcd. for [M + H]⁺ C₅₀H₅₇N₈O₃:817.4554; found 817.4589. M49 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

1.67 min (Cond. 2); 92%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₄:743.40; found 743.42; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₄:743.4033; found 743.4053. M50 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate

1.63 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₉N₈O₄:729.39; found 729.39; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₉N₈O₄:729.3877; found 729.3888. M51 (1R)-N,N-diethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(4-morpholinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine

1.67 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₃:727.41; found 727.40; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₃:727.4084; found 727.4117. M52 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1- phenylethanamine

1.65 min (Cond. 2); 92%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₅N₈O₂:775.44; found 775.48; HRMS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₅N₈O₂:775.4448; found 775.4433. M53 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

1.68 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₄:743.40; found 743.42; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₄:743.4033; found 743.4055. M54 methyl ((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

1.78 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.42; found 757.42; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.4190; found 757.4216. M55 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

1.74 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.42; found 757.41; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄:757.4190; found 757.4212. M56 methyl ((1R)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate

1.74 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.42; found 769.52; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.4190; found 769.4188. M57 methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate

1.72 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.42; found 769.53; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.4190; found 769.4218. M58 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.76 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₅N₈O₄:771.43; found 771.54; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:771.4346; found 771.4379. M59 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2,2- dimethylpropyl)carbamate

1.92 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₇N₈O₆:785.45; found 785.63; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄:785.4503; found 785.4515. M60 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-buten-1- yl)carbamate

1.81 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.42; found 769.55; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₃N₈O₄:769.4190; found 769.4157. M61 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2- oxoethyl)carbamate

1.73 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₅:773.41; found 773.55; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₅:773.4139; found 773.4107. M62 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate

1.73 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₅N₈O₄:771.43; found 771.56 (M + H)⁺; HRMS: Anal. Calcd. for [M + H]⁺C₄₅H₅₅N₈O₄: 771.4346; found 771.4315.

Example M63-M66

Example M63-M66x were prepared from 28f and the respective acids usingthe method described for Example 28. Products were prepared as TFA saltsunless noted otherwise.

Example Compound Name

RT (LC-Cond.); % homogeneity index; MS data M63 methyl((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.17 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₄:743.40; found 743.41; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₁N₈O₄:743.4033; found 743.4017 M64 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.22 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₅N₈O₄:771.43; found 771.39; HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₅N₈O₄:771.4346; found 771.4361 M65 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1H-imidazol-5-ylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

1.15 min (Cond. 1); >90%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₀N₉O₄:710.32; found 710.31; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₀N₉O₄:710.3203; found 710.3180 M66a & M66b M66a: methyl((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(4-(diethylamino)-2-((methoxycarbonyl)amino)butanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

Two fractions enriched with one of two compounds exhibiting very similarspectral data were isolated. M66a: 1.19 min (Cond. 1); 97%; LC/MS: Anal.Calcd. for [M + H]⁺ C₄₆H₅₆N₉O₆: 830.44; found 830.39 M66b: 1.21 min(Cond. 1); >97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₆N₉O₆: 830.44;found 830.39; HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₆N₉O₆: 830.4354;found 830.4316 M66x (AcOH) methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

1.80 minutes (Cond. 2); (98%); LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₅₃N₈O₄ 757.42; found 757.48; HRMS: Anal. Calcd for [M + H]⁺C₄₄H₅₃N₈O₄: 757.4190; found 757.4156

Example M67-M91

Example M67-M91y were prepared from 28d and the respective acids usingthe method described for Example 28. Final products were prepared as TFAsalts, unless noted otherwise.

Example Compound Name

RT (LC-Cond.); % homogeneity index; MS data M67a & M67b M67a: methyl((1S)-1- (((2S)-2-(5-(4′-(2-((2S)-1-(4- (diethylamino)-2-((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Two fractions enriched with one of two compounds exhibiting very similarspectral data were isolated M67a: 1.16 min (Cond. 1); >98%; LC/MS: Anal.Calcd. for [M + H]⁺ C₄₃H₅₈N₉O₆: 796.45; found 796.40 M67b: 1.17 min(Cond. 1); >96%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₈N₉O₆: 796.45;found 796.40; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₈N₉O₆: 796.4510;found 796.4537 M68 (•AcOH) methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-(4- morpholinyl)propyl)carbamate

1.10 min (Cond. 1); >96%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₆N₉O₇:810.43; found 810.44; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₅₆N₉O₇:810.4303; found 810.4333 M69 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

1.72 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄:709.42; found 709.56; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄:709.4190; found 709.4219. M70 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

1.75 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄:709.42; found 709.55; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄:709.4190; found 709.4184. M71 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1- (methoxymethyl)-2- oxoethyl)carbamate

1.81 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₇:741.37; found 741.48; HRMS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₇:741.3724; found 741.3738. M72 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3,3-dimethylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

2.07 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₃N₈O₆:753.41; found 753.53; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₃N₈O₆:753.4088; found 753.4111. M73 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

1.80 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₇H₄₅N₈O₆:697.35; found 697.32; HRMS: Anal. Calcd. for [M + H]⁺ C₃₇H₄₅N₈O₆:697.3462; found 697.3443. M74 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

1.90 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₆:725.37; found 725.36; HRMS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₆:725.3775; found 725.3742. M75 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl) carbamate

1.96 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₆:739.39; found 739.37; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₆:739.3932; found 739.3953. M76 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3- buten-1-yl)carbamate

1.91 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₉N₈O₆:737.38; found 737.38; HRMS: Anal. Calcd. C₄₀H₄₉N₈O₆: 737.3775; found737.3744. M77 methyl ((1S)-1-(((2S)-2-(5-(4′- (2-((2S)-1-((2S)-2-cyclopropyl-2- ((methoxycarbonyl)amino) acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate

1.90 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₉N₈O₆737.38; found 737.34; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₉N₈O₆737.3775; found 737.3764. M78 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (ethyl(methyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate

1.82 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄757.42; found 757.42; HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₅₃N₈O₄757.4190; found 757.4188. M79 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-valyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

1.78 min (Cond. 2); 94%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄737.45; found 737.45; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄737.4503; found 737.4488. M80 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)- 2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

2.05 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₉N₈O₆773.37; found 773.40; HRMS: Anal. Calcd. for [M + H]⁺ C₄₃H₄₉N₈O₆773.375; found 773.3759. M81 methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(3- methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl) carbamate

2.05 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₈N₇O₄666.38; found 666.37; HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₈N₇O₄666.3768; found 666.3785. M82 methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1- ((4-methyl-1- piperazinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl) carbamate

1.75 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₅₀N₉O₄708.40; found 708.38; HRMS: Anal. Calcd. for [M + H]⁺ C₃₉H₅₀N₉O₄708.3986; found 708.3974. M83 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N- dipropyl-D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

1.81 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄737.45; found 737.47; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄737.4503; found 737.4480. M84 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N- dipropyl-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

1.78 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄737.45; found 737.47; HRMS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₇N₈O₄737.4503; found 737.4491. M85 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.76 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₄723.43; found 723.47; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₄723.4346; found 723.4335. M86 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- (diethylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.73 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₄723.43; found 723.47; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₄723.4346; found 723.4343. M87 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(1H-imidazol- 4-ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.67 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₇H₄₂N₉O₄676.34; found 676.45; HRMS: Anal. Calcd. for [M + H]⁺ C₃₇H₄₂N₉O₄676.3360; found 676.3344. M88 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl- O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.67 min (Cond. 2); 97%; LCMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₅739.43; found 739.54; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₅739.4295; found 739.4327. M89 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N²,N²- diethyl-D-asparaginyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.76 min (Cond. 2); 97%; LCMS: Anal. Calcd. for for [M + H]⁺ C₄₁H₅₄N₉O₅752.42; found 752.43; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₄N₉O₅752.4248; found 752.4263. M90 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2R)-1-((2R)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

2.00 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₆739.39; found 739.46; HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₁N₈O₆739.3932; found 739.3901. M91 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl- O-methyl-D-seryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.73 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₅739.43; found 739.39; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₅₅N₈O₅739.4295; found 739.4277. M91x methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl- 3-methyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.78 minutes (Cond. 2); (97%); LC/MS: Anal. Calcd.for [M + H]⁺C₄₃H₅₉N₈O₄ 751.47; found 751.50; HRMS: Anal. Calcd for [M + H]⁺C₄₃H₅₉N₈O₄: 751.4659; found 751.4648. M91y methyl ((1S)-3-amino-1-(((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-3- oxopropyl)carbamate (non-preferred name)

1.92 min (Cond. 2); (>97%); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₈N₉O₇754.37; found 754.42; HRMS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₈N₉O₇:754.3677; found 754.3676.

Example M92-M103

Example M92-M103 were prepared from 28d and the respective acids usingthe method described for Example 28. Final products were prepared as TFAsalts, unless noted otherwise.

R Example Compound Name (Source) Analytical Data M92 methyl((1S)-1-methyl-2-((2S)- 2-(5-(4′-(2-((2S)-1-(1,3-oxazol-2-ylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)carbamate

1.70 min (Cond. 2); 95%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₃₇N₈O₅649.29; found 649.41; HRMS: Anal. Calcd for [M + H]⁺ C₃₅H₃₇N₈O₅649.2887; found 649.2867 M93 methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate

1.76 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₅N₈O₆709.35; found 709.50; HRMS: Anal. Calcd for [M + H]⁺ C₃₈H₄₇N₈O₆709.3462; found 709.3478 M94 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)butyl) carbamate

1.84 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₈O₆711.36; found 711.54; HRMS: Anal. Calcd for [M + H]⁺ C₃₈H₄₇N₈O₆711.3619; found 711.3590. M95 methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)- 2,2-dimethylpropyl)carbamate

1.91 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₆725.37; found 725.54; HRMS: Anal. Calcd for [M + H]⁺ C₃₉H₄₉N₈O₆725.3775; found 725.3809. M96 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D- alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.61 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₉N₈O₄681.39; found 681.54; HRMS: Anal. Calcd for [M + H]⁺ C₃₈H₄₉N₈O₄681.3877; found 681.3867. M97 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(7- azabicyclo[2.2.1]hept-7- yl(phenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl- 2-oxoethyl)carbamate

1.72 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₅₁N₈O₄767.40; found 767.59; HRMS: Anal. Calcd for [M + H]⁺ C₄₅H₅₁N₈O₄767.4033; found 767.4067. M98 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-hydroxy-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.80 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₂N₇O₅688.32; found 688.48; HRMS: Anal. Calcd for [M + H]⁺ C₃₉H₄₂N₇O₅688.3247; found 688.3263. M99 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (ethyl(methyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

1.70 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₄₉N₈O₄729.39; found 729.56; HRMS: Anal. Calcd for [M + H]⁺ C₄₂H₄₉N₈O₄729.3877; found 729.3887. M100 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1- (methoxymethyl)-2- oxoethyl)carbamate

1.75 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₇H₄₅N₈O₇713.34; found 713.34; HRMS: Anal. Calcd for [M + H]⁺ C₃₇H₄₅N₈O₇713.3411; found 713.3386. M101 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D- valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.66 min (Cond. 2); 94%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄709.42; found: 709.42; HRMS: Anal. Calcd for [M + H]⁺ C₄₀H₅₃N₈O₄709.4190; found 709.4166. M102 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-D- alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.71 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄709.42; found 709.48; HRMS: Anal. Calcd for [M + H]⁺ C₄₀H₅₃N₈O₄709.4190; found 709.4191. M103 methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-L- alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.66 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₃N₈O₄709.42; found 709.42; HRMS: Anal. Calcd for [M + H]⁺ C₄₀H₅₃N₈O₄709.4190; found 709.4198.

Example M104 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(3-hydroxy-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M104 Step a

Pyrrolidine M104a was prepared from intermediate 28d and Cap-51according to the procedure described for the synthesis of pyrrolidine28f

Example M104

HATU (96.3 mg, 0.253 mmol) was added to a DMF (5.0 mL) solution ofpyrrolidine M104a (150 mg, 0.217 mmol),(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (65.8mg, 0.282 mmol) and i-Pr₂EtN (180 uL, 1.03 mmol), and the reactionmixture was stirred at ambient condition for 35 min. The volatilecomponent was removed in vacuo, and the residue was purified with areverse phase HPLC (MeOH/H₂O/TFA), and the fractions were concentratedin vacuo. The resultant residue was treated with 25% TFA/CH₂Cl₂ (6.0 mL)and stirred for 3.25 hr. The volatile component was removed in vacuo andthe residue was free-based (MCX; MeOH wash; 2.0 M NH₃/MeOH elution) toafford Example M104 as an off-white foam (107 mg). LC (Cond. 2): RT=1.03min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₃₈H₄₉N₈O₅=697.38. found 697.28.

Example M105 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Methyl chloroformate (20 μL, 0.258 mmol) was added to a THF (2.0 mL)solution of Example M104 (82.9 mg, 0.119 mmol) and i-Pr₂EtN (50 uL,0.287 mmol) and stirred for 65 min. The mixture was then treated with2.0 M NH₃/MeOH (3 mL), stirred for 2.75 hr, and the volatile componentwas removed in vacuo. The resultant residue was purified with a reversephase HPLC (MeOH/H₂O/TFA) to afford the TFA salt of Example M105 as awhite foam (64.1 mg). LC (Cond. 2): RT=1.17 min; >98% homogeneity index;LC/MS: Anal. Calcd. for [M+H]⁺ C₄₀H₅₁N₈O₇=755.39. found 755.25.

Example M106 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-4-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (69 mg, 0.181 mmol) was added to a DMF (3.0 mL) solution ofpyrrolidine M104a (101 mg, 0.173 mmol), Cap-80b (55.9 mg, ˜0.183 mmol)and i-Pr₂EtN (90 μL, 0.515 mmol), and the reaction mixture was stirredat ambient condition for 70 min. The volatile component was removed invacuo and the residue was purified with a reverse phase HPLC(H₂O/MeOH/TFA) to retrieve the dominant signal. The collected fractionwas allowed to stand at ambient condition for a few hours and then thevolatile component was removed in vacuo, at which time totaldesilylation of the coupled product was achieved. The resultant productwas submitted to a reverse phase HPLC purification (ACN/H₂O/NH₄OAc) toafford Example M106 as an off-white foam (32.2 mg). LC (Cond. 2):RT=1.19 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₀H₅₁N₈O₇=755.39. found 755.85.

Example M107 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3S)-4-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M107 was prepared from pyrrolidine M104a and Cap-80a accordingto the procedure described for the synthesis of Example M106. LC (Cond.2): RT=1.20 min; ˜95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₀H₅₁N₈O₇=755.39. found 755.78.

Example M108 methyl((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-L-valyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

HATU (70.1 mg, 0.184 mmol) was added to a DMF (3.0 mL) solution ofpyrrolidine M104a (100.7 mg, 0.173 mmol), (L)-Boc-Valine (49.6 mg, 0.228mmol) and i-Pr₂EtN (70 uL, 0.40 mmol), and the reaction mixture wasstirred at ambient condition for 65 min. The volatile component wasremoved in vacuo and the residue was purified with a Biotage (60-100%EtOAc/hexanes) to afford 116.6 mg of the coupled product.

The above product (112 mg) was treated with 25% TFA/CH₂Cl₂ (2 mL) andthe reaction mixture was stirred for 6 hr. The volatile component wasremoved in vacuo and the crude material was purified with a combinationof MCX resin (MeOH wash; 2.0 M NH₃/MeOH elution) and reverse phase HPLC(H₂O/MeOH/TFA) to afford the TFA salt of Example M108 as a white foam(98.5 mg). LC (Cond. 2): RT=1.14 min; >98% homogeneity index; LC/MS:Anal. Calcd. for [M+H]⁺ C₃₈H₄₉N₈O₄=681.39. found 681.36. HRMS Calcd. for[M+H]⁺ C₃₈H₄₉N₈O₄: 681.3877. found 681.3865.

Example M109 (R=Bn) & M110 (R=Me) M109: benzyl(3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoateM110: methyl(3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoate

HATU (109 mg, 0.287 mmol) was added to DMF (1.5 ml) solution ofpyrrolidine M104a (151 mg, 0.260 mmol), Cap-68 (109 mg, 387 mmol), andi-Pr₂EtN (100 μl, 0.574 mmol), and the reaction mixture was stirred atambient condition for 3 hr. The volatile component was removed in vacuoand crude material was purified with a combination of MCX resin (MeOHwash; 2.0 M NH₃/MeOH elution) and reverse phase HPLC (H₂O/MeOH/TFA) toafford the TFA salt Example M109 (88.0 mg) and Example M110 (90.2 mg).Example M109: LC (Cond. 2): RT=2.16; 97% homogenity index; LC/MS: Anal.Calcd. for [M+H]⁺ C₄₆H₅₃N₈O₈: 845.40. found 845.51. HRMS Calcd. for[M+H]⁺ C₄₆H₅₃N₈Os: 845.3986. found 845.3983. Example M110: LC (Cond. 2):RT=1.92; 97% homogenity index; LC/MS: Anal. Calcd. for [M+H]⁺C₄₀H₄₉N₈O₄: 769.47. found 769.46. HRMS Calcd. for [M+H]⁺ C₄₀H₄₉N₈O₄:769.3673. found 769.3682.

Example M111(3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoicacid

A mixture of Example M109 (69.7 mg, 0.082 mmol) and 10% Pd/C (10 mg) inmethanol (5 ml) was stirred at room temperature under a balloon of H₂for 1.5 h. The reaction was filtered through diatomaceous earth(Celite®) and concentrated in vacuo, and the resultant material waspurified with a reverse phase HPLC (H₂O/MeOH/TFA) to afford the TFA saltof Example M111 as an off-white foam (54.0 mg). LC (Cond. 2): RT=1.18;99% homogenity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₉H₄₇N₈O₈: 755.35.found 755.32. HRMS Calcd. for [M+H]⁺ C₃₉H₄₇N₈O₈: 755.3517. found755.3525.

Example M112 methyl((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-4-(4-methyl-1-piperazinyl)-4-oxobutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

HATU (30.6 mg, 0.080 mmol) was added to a DMF (1.5 ml) solution ofExample M111 (55.3 mg, 0.0733 mmol), N-methyl piperazine (11.0 mg, 0.11mmol) and i-Pr₂EtN (25 μl, 0.14 mmol), and the reaction mixture wasstirred at ambient condition for 1.5 h. All volatile components wereremoved in vacuo, and the residue was purified with a combination of MCXresin and a reverse phase HPLC (H₂O/MeOH/TFA) to afford the TFA salt ofExample M112 as an off-white foam (51.4 mg). LC (Cond. 2): RT=1.75; 91%homogenity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₄H₅₇N₁₀O₇: 837.44.found 837.59. HRMS Calcd. for [M+H]⁺ C₄₄H₅₇N₁₀O₇: 837.4412. found837.4453.

Example M113 methyl((1S)-3-(dimethylamino)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-oxopropyl)carbamate

Example M118 was prepared from Example M111 and Me₂N.HCl according tothe procedure described for Example M112. LC (Cond. 2): RT=1.89; 99%homogenity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₂N₉O₇: 782.40.found 782.47. HRMS Calcd. for [M+H]⁺ C₄₁H₅₂N₉O₇: 782.3990. found782.4008.

Example M1144,4′-bis(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-biphenylcarboxylicacid

Example M114 Step a

DMF (20 mL) was added to mixture of KHCO₃ (1.84 g, 18.4 mmol) and2-bromo-5-iodobenzoic acid (4.99 g, 15.3 mmol) and the resulting mixturewas stirred for 15 min. Benzyl bromide (2.4 mL, 20.2 mmol) was addeddrop-wise over 5 min and stirring was continued at ambient condition for˜20 hr. Most of the volatile component was removed in vacuo and theresidue was partitioned between CH₂Cl₂ (50 mL) and water (50 mL), andthe organic layer was washed with water (50 mL), dried (MgSO₄),filtered, and concentrated. The resulting crude material was purifiedwith flash chromatography (7% EtOAc/hexanes) to afford ester M114a as acolorless viscous oil (6.01 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ8.07 (d, J=2.0, 1H), 7.81 (dd, J=8.4, 2.1, 1H), 7.53 (d, J=8.4, 1H),7.48 (m, 2H), 7.43-7.34 (m, 3H), 5.34 (s, 2H). LC (Cond. 1): RT=2.1 min;LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₄H₁₀BrINaO₂: 438.88. found 438.83.

Example M114 Step b-d

Ester M114a was elaborated to ester M114d by employing a three stepprotocol employed in the synthesis of bromide 121c from1-bromo-4-iodo-2-methylbenzene. M114d: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400MHz): δ 12.04/11.97 (br s, 1H), 8.12 (d, J=2.0, 0.92H), 7.99 (app br s,0.08H), 7.81 (dd, J=8.3, 2.0, 0.92H), 7.74-7.62 (m, 2.08H), 7.50 (app brd, J=7.0, 2H), 7.44-7.35 (m, 3H), 5.38 (s, 2H), 4.79 (m, 1H), 3.52 (appbr s, 1H), 3.36 (m, 1H), 2.24-1.79 (m, 4H), 1.39/5.11 (two s, 9H). LC(Cond. 1): RT=1.66 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₆H₂₉BrN₃O₄:526.13. found 526.16.

Example M114 Step e

Ester M114e was prepared from bromide M114d and boronate 1c according tothe preparation of dimer 1d. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ12.18/12.00/11.91/11.83 (four br s, 2H), 8.11-7.03 (m, 14H), 5.10 (s,2H), 4.85-4.78 (m, 2H), 3.55 (app br s, 2H), 3.37 (m, 2H), 2.29-1.80 (m,8H), 1.41/1.16 (two s, 18H). LC (Cond. 1): RT=1.54 min; LC/MS: Anal.Calcd. for [M+H]⁺ C₄₄H₅₁N₆O₆: 759.39. found 759.63.

Example M114 Step f

A mixture of benzyl ester M114e (1.005 g, 1.325 mmol) and 10% Pd/C (236mg) in MeOH (20 mL) was stirred under a balloon of H₂ for 5 hr. Thereaction mixture was then treated with a 1:1 mixture of MeOH and CH₂Cl₂,filtered through a pad of diatomaceous earth (Celite®-521), and thefiltrate was rotervaped to afford acid M114f (840 mg), contaminated withPh₃PO which was a carryover from the Suzuki coupling step. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.17/11.98/11.89/11.81 (four app br s,2H), 8.04-7.31 (m, 9H), 4.85-4.78 (m, 2H), 3.55 (app br s, 2H), ˜3.37(m, 2H, overlapped with water signal) 2.27-1.84 (m, 8H), 1.41/1.16 (twos, 18H). LC (Cond. 1): RT=1.37 min; LC/MS: Anal. Calcd. for [M+H]⁺C₃₇H₄₅N₆O₆: 669.34. found 669.53.

Example M114 Step g

4N HCl/dioxane (8.0 mL) and CH₂Cl₂ (2.0 mL) were sequentially added tocarbamate M114f (417 mg, 0.623 mmol), the mixture was vigorously stirred5.5 hr, and then the volatile component was removed in vacuo to affordthe HCl (0.4×) salt of pyrrolidine M114g (487 mg), contaminated withPh₃PO impurity. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz) after D₂O exchange:δ 8.23 (d, J=1.7, 1H), 8.09-8.04 (m, 3H), 7.92 (d, J=8.3, 2H), 7.53 (d,J=8.1, 1H), 7.48 (d, J=8.3, 2H), 5.00 (app br t, J=8.3, 1H), 4.90 (appbr t, J=8.4, 1H), 3.6-3.3 (m, 4H), 2.5-1.99 (m, 8H). LC (Cond. 1):RT=0.92 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₇H₂₉N₆O₂: 469.24. found469.31.

Example M114

HATU (79.9 mg, 0.21 mmol) was added to a DMF (3.0 mL) solution ofpyrrolidine M114g. 4HCl (80 mg, 0.13 mmol), Cap-51 (92.4 mg, 0.527 mmol)and i-Pr₂EtN (160 μL, 0.919 mmol), and the reaction mixture was stirredat ambient condition for 2 hr. The volatile component was removed invacuo and the residue was purified with a combination of MCX (MeOH wash;2.0 M NH₃/MeOH elution) and a reverse phase HPLC (CH₃CN/H₂O/NH₄OAc) toafford the acetic acid salt of Example M114. LC (Cond. 1): RT=1.20min; >98 homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₁N₈O₈:783.38. found 783.34. HRMS Calcd. for [M+H]⁺ C₄₁H₅₁N₈O₈: 783.3830. found783.3793.

Example M115-M116

Examples M115-M116 were prepared using the same method as described forExample M114 and by substituting the appropriate acids for Cap-51. Theproducts were isolated as either the acetic acid or TFA salt dependingon the nature of the mobile phase of the HPLC purification step.

    Example     Compound Name

RT (LC-Cond.); % homogeneity index; MS data M115 (AcOH)4,4′-bis(2-((2S)-1-((2R)- 2-cyclopropyl-2- ((methoxycarbonyl)amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- biphenylcarboxylicacid

1.17 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₇N₈O₈:779.35; found 779.33; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₇N₈O₈:779.3517; found 779.3498 M116 (2.TFA) 4,4′-bis(2-((2S)-1-((2S)-2-cyclopropyl-2- ((methoxycarbonyl) amino)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2- biphenylcarboxylic acid

1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₇N₈O₈:779.35; found 779.33; HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₇N₈O₈:779.3517; found 779.3551 M117 (2.TFA) 4,4′-bis(2-((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-2- biphenylcarboxylic acid

1.29 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₇H₄₇N₈O₈:851.35; found 851.33; HRMS: Anal. Calcd. for [M + H]⁺ C₄₇H₄₇N₈O₈:851.3517; found 851.3480

Example M18 methyl((1S)-1-(((2S)-2-(5-(2′-carbamoyl-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Et₃N (300 μL, 2.15 mmol) was added to a mixture of acid M114f (198.3 mg,0.297 mmol), HOBt (94.2 mg, 0.697 mmol), EDCI (0.66 mmol), NH₄Cl (101mg, 1.89 mmol) in DMF (8.0 mL) and stirred for 17 hr at ambientcondition. The reaction mixture was filtered through 0.45 μm filter, thevolatile component was removed in vacuo and the residue was partitionedbetween CH₂Cl₂ and water. The organic layer was concentrated and theresulting crude material was purified with a reverse phase HPLC(MeOH/H₂O/TFA).

The above product was treated with 25% TFA/CH₂Cl₂ (4.0 mL) and thereaction mixture was stirred for 2.5 hr at ambient condition. Thevolatile component was removed in vacuo and the residue was free-based(MCX; MeOH wash; 2.0 M NH₃/MeOH elution) to afford amide M118a (67.2mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 11.83 (br s, 2H), 7.81-7.80(m, 2H), 7.73 (d, J=8.3, 2H), 7.65 (br s, 1H), 7.52 (br S, 1H), 7.44 (brs, 1H), 7.41 (d, J=8.3, 2H), 7.36 (d, J=8.3, 1H), 7.31 (br s, 1H), 4.16(app t, J=7.2, 2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m,2H), 1.94-1.85 (m, 2H), 1.83-1.66 (m, 4H). LC (Cond. 1): RT=0.89min; >95 homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₂₇H₃₀N₇O:468.25. found 468.24.

Example M118

The TFA salt of Example 118 was prepared from intermediate M118a andCap-51 according to the procedure described for Example 1. LC (Cond. 1):RT=1.16 min; 97% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺C₄₁H₅₂N₉O₇: 782.40. found 782.40. HRMS: Anal. Calcd. for [M+H]⁺C₄₁H₅₂N₉O₇: 782.3990. found 782.3979.

Example M19 methyl((1S)-1-(((2S)-2-(5-(2-(hydroxymethyl)-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M119 Step a

DIBAL-H (8.0 mL of 1.0 M/CH₂Cl₂, 8.0 mmol) was added drop-wise to anice-water cooled CH₂Cl₂ (20 mL) solution of benzyl ester M114e (1.216 g,1.60 mmol), and the reaction mixture was stirred for 1 hr and anadditional DIBAL-H (0.5 mL of 1.0 M/CH₂Cl₂, 0.5 mmol) was added andstirring was continued for ˜2.5 hr. The reaction was quenched withexcess saturated NH₄Cl solution and the mixture was diluted with waterand extracted with CH₂Cl₂ (3×). The combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo. The resulting crudematerial was purified with a Biotage (100 g silica gel; 2-6% MeOH/EtOAc)to afford alcohol M119a as an off-white foam (610 mg). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 400 MHz): δ 12.23 (br s, 0.19H), 12.17 (br s, 0.19H), 11.89(br s, 0.81H), 11.82 (br s, 0.81H), 7.97 (s, 0.81H), 7.84 (s, 0.19H),7.78 (d, J=8.1, 1.62H), 7.69-7.20 (m, 6.38H), 5.21-5.15 (m, 1H),4.86-4.78 (m, 2H), 4.49-4.45 (m, 2H), ˜3.54 (m, 2H), 3.40-3.34 (m, 2H),2.30-1.80 (m, 8H), 1.41/1.17 (two s, 18H). LC (Cond. 1): RT=1.36 min.LC/MS: Anal. Calcd. for [M+H]⁺ C₃₇H₄₇N₆O₅: 655.36. found 655.34.

Example M119 Step b

25% TFA/CH₂Cl₂ (3.0 mL) was added to carbamate M119a (105 mg, 0.160mmol) and the mixture was stirred at ambient condition for 4.5 hr. Thevolatile component was removed in vacuo and the residue was free-based(MCX; MeOH wash; 2.0 M NH3/MeOH elution) to afford pyrrolidine M119b,contaminated with its trifluoroacetylated derivative of unknownregiochemistry. The sample was dissolved in MeOH (1.5 mL) and treatedwith 1.0 M NaOH/H₂O (300 μL, 0.3 mmol) and the mixture was stirred for2.75 hr. It was then directly submitted to MCX purification (MeOH wash;2.0 M NH₃/MeOH elution) to afford M119b as a film of white solid (63.8mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 11.82 (br s, 2H), 7.96 (s,1H), 7.77 (d, J=8.0, 2H), 7.66 (d, J=8.0, 1H), 7.46 (br s, 1H), 7.42 (brs, 1H), 7.36 (d, J=8.0, 2H), 7.21 (d, J=8.0, 1H), 5.16 (app br s, 1H),4.46 (s, 2H), 4.16 (app t, J=7.1, 2H), 3.00-2.82 (two m, 4H; there is abroad base line signal in this region from the pyrrolidine NH that wasnot included in the integration), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H),1.83-1.67 (m, 4H). LC (Cond. 1): RT=0.78 min. LC/MS: Anal. Calcd. for[M+H]⁺ C₂₇H₃₁N₆O: 455.26. found 455.27.

Example M119

Example M119 was prepared from M119b and Cap-51 according to theprocedure described for Example 1, with the exception that a reversephase HPLC with ACN/H₂O/NH₄OAC solvent system was employed for thepurification step. LC (Cond. 1): RT=1.15 min; 98% homogeneity index.LC/MS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₃N₈O₇: 769.40. found 769.40. HRMS:Anal. Calcd. for [M+H]⁺ C₄₁H₅₃N₈O₇: 769.4037. found 769.4023.

Example M120 methyl((1S)-1-(((2S)-2-(5-(2-((dimethylamino)methyl)-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M120 Step a

CH₂Cl₂ (6.0 mL) was added to a mixture alcohol M119a (501 mg, 0.765mmol), TPAP (29.1, 0.083 mmol) and 4-methylmorpholine N-oxide (135.8 mg,1.159 mmol), and the resultant heterogeneous mixture was vigorouslystirred at ambient condition for 14.5 hr. Additional TPAP (11.0 mg,0.031 mmol) and 4-methylmorpholine N-oxide (39 mg, 0.33 mmol) were addedand stirring was continued for an additional 24 hr. The mixture wasfiltered through diatomaceous earth (Celite®), the filtrate wasrotervaped and the resulting crude material was purified with a Biotage(2% MeOH/EtOAc) to afford aldehyde M120a as a yellow viscous oil (195.6mg). LC (Cond. 1): RT=1.37 min. LC/MS: Anal. Calcd. for [M+H]⁺C₃₇H₄₅N₆O₅: 653.35. found 653.40.

Example M120 Step b

NaCNBH₃ (33 mg, 0.50 mmol) was added in one batch to a MeOH (3.0 mL)solution of aldehyde M120a (195.6 mg, 0.30 mmol) and Me₂NH (200 μL of40% solution in H₂O), and the reaction mixture was stirred for 4 hr. Thevolatile component was removed in vacuo and the residue was purifiedwith a flash chromatography (sample was loaded as a silica gel mesh;3-15% MeOH/CH₂Cl₂) to afford amine M120b as an off-white foam (120 mg).LC (Cond. 1): RT=1.32 min. LC/MS: Anal. Calcd. for [M+H]⁺ C₃₉H₅₂N₇O₄:682.41. found 682.42.

Example M120 Step c

Carbamate M120b was converted to M120c by employing the protocoldescribed for the preparation of 1e from 1d. ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz): δ 11.82 (br s, 2H), 7.87 (s, 1H), 7.77 (d, J=8.0, 2H), 7.65(d, J=7.8, 1H), 7.45/7.43 (overlapping two br s, 2H), 7.37 (d, J=7.8,2H), 7.21 (d, J=7.8, 1H), 4.87 (m, 0.1H), 4.17 (m, 1.90H), ˜3.3 (signalof Me₂NCH₂ overlapped with that of water), 3.01-2.94 (m, 2H), 2.89-2.83(m, 2H), 2.10 (s, 6H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.81-1.67(m, 4H). LC (Cond. 1): RT=0.79 min. LC/MS: Anal. Calcd. for [M+H]⁺C₂₉H₃₆N₇: 482.30. found 482.35.

Example M120

The TFA salt of Example M120 was prepared from pyrrolidine M120c andCap-51 according to the procedure described for Example 1. LC (Cond. 1):RT=1.06 min; 96% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺C₄₃H₅₈N₉O₆: 796.45. found 796.48. HRMS: Anal. Calcd. for [M+H]⁺C₄₃H₅₈N₉O₆: 796.4510. found 796.4515.

Example M121 dimethyl((2-((dimethylamino)methyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

The TFA salt of Example M121 was prepared from M120c and Cap-4 accordingto the procedure described for Example 1. LC (Cond. 1): RT=1.15min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₉H₅₄N₉O₆:796.45. found 864.46. HRMS: Anal. Calcd. for [M+H]⁺ C₄₉H₅₄N₉O₆:864.4197. found 864.4222.

Example M122 methyl((1S)-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

Example M122 Step a

Diisopropyl ethylamine (1.81 mL, 10.4 mmol) was slowly added toacetonitrile (20 mL) solution of(1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.10]hexane-3-carboxylicacid (2.36 g, 10.4 mmol) and(2-(4′-(2-bromoacetyl)biphenyl-4-yl)-2-oxoethyl)bromonium (2.0 g, 5.05mmol), and the reaction mixture was stirred at ambient conditions for 16hr. The solvent was evaporated and the residue was partitioned betweenethyl acetate and water (1:1, 40 mL each). The organic layer was washedwith Sat. NaHCO₃ (2×10 mL), brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to afford ketoester M122a (3.58 g) as a viscousamber oil, which solidified upon storage in a refrigerator. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 8.20 (m, 4H), 7.97 (d, J=8.5, 4H),5.71-5.48 (m, 4H), 4.69 (m, 2H), 3.44 (m, 2H), 3.3 (m, 2H), 2.76-2.67(m, 2H), 2.27 (m, 2H), 1.60 (m, 2H), 1.44/1.38 (two s, 18H), 0.78 (m,2H), 0.70 (m, 2H). LC (Cond. 1): RT=1.70 min; LC/MS: the molecular ionwas not picked up.

Example M122 Step b

Ammonium acetate (2.89 g, 37.5 mmol) was added to a toluene (20 mL)solution of ketoester M122a (2.58 g, 3.75 mmol), and the resultingmixture was heated at 120° C. for 4.5 hr, while azaetroping the waterthat is formed with a Dean-Stark set-up. The reaction mixture was cooledto room temperature and the volatile component was removed in vacuo.Sat. NaHCO₃ solution (10 mL) was added to the solid and the mixture wasstirred for 30 min, and the solid was filtered, dried in vacuo andsubmitted to a Biotage purification (28-100% EtOAc/hexanes) to affordimidazole M122b as light yellow solid (0.6 g). LC (Cond. 1): RT=1.52min; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₅N₆O₄: 649.35. found 649.78.

Example M122 Step c

4 N HCl in dioxane (5 mL) was added to a ice-water cooled dioxane (16mL) solution of carbamate M122b (0.8 g, 1.2 mmol), the ice-water bathwas removed and the mixture was stirred at ambient condition for 4 hr.Big chunks of solid that formed during the reaction were broken up witha spatula. Removal of the volatile component in vacuo affordedpyrrolidine M122c (0.4HCl) as yellow solid (0.73 g).

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.90 (d, J=8.3, 4H), 7.84 (br s,2H), 7.79 (d, J=8.3, 4H), 5.24 (m, 2H), 3.38 (m, 2H), 2.71 (m, 2H),˜2.50 (2H, overlapped with solvent signal), 1.93 (m, 2H), 1.38 (m, 2H),0.96 (m, 2H). LC (Cond. 1): RT=1.03 min; LC/MS: Anal. Calcd. for [M+H]⁺C₂₈H₂₉N₆: 449.25. found 449.59.

Example M122

The TFA salt of Example M122 was prepared from M122c and Cap-51according to the procedure described for Example 1. LC (Cond. 1):RT=1.34 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₅₁N₈O₆: 763.39. found763.73.

Example M123-M130

Example M123-M130 were prepared according to the procedure described forExample M122. Example M123-M129 were prepared as TFA salts, where asExample M130 was prepared as a free base.

    Example     Compound Name

RT (LC-Cond.); % homogeneity index; MS data M123 methyl((1R)-1-(((1S,3S,5S)-3-(5- (4′-(2-((1S,3S,5S)-2-((2R)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2- yl)carbonyl)-2-methylpropyl)carbamate

1.372 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₅₁N₈O₆: 763.39; found 763.73 M124 dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(1S,3S,5S)-2- azabicyclo[3.1.0]hexane-3,2-diyl((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate

2.28 minutes (Cond. M1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₈H₄₇N₈O₆: 831.36; found 831.36 M125 methyl ((1S)-2-hydroxy-1-(((1S,3S,5S)-3-(5-(4′-(2- ((1S,3S,5S)-2-((2S)-3-hydroxy-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2- yl)carbonyl)-2-methylpropyl)carbamate

1.76 minutes (Cond. M1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₅₁N₈O₈: 795.38; found 795.37 M126 dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(1S,3S,5S)-2- azabicyclo[3.1.0]hexane-3,2-diyl((2S)-1-oxo-1,2- butanediyl)))biscarbamate

1.25 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₇N₈O₆: 735.36; found 735.68 M127 dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(1S,3S,5S)-2- azabicyclo[3.1.0]hexane-3,2-diyl((1S)-1-cyclopropyl-2- oxo-2,1-ethanediyl))) biscarbamate

1.27 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₆: 759.36; found 759.72 M128 methyl ((1S)-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2S)-2- ((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2- azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2- yl)carbonyl)-2,2- dimethylpropyl)carbamate

2.48 minutes (Cond. M1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₅₅N₈O₆: 791.42; found 791.41 M129 methyl (2-((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2- (((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2-yl)-2- oxoethyl)carbamate

1.10 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₆H₃₉N₈O₆: 679.74; found 679.77 M130 methyl ((1S)-2-((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-(N- (methoxycarbonyl)-L-alanyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2-yl)-1-methyl-2-oxoethyl)carbamate

1.16 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₃N₈O₆: 707.33; found 707.69

Example M131 methyl((1S)-1-(((1R,3R,5R)-3-(5-(4′-(2-((1R,3R,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

Example M131 was prepared according to the procedure described for itsdiastereomer Example M122 starting from(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, which was in turn synthesized by employing a literature protocol(Hanessian et al., Angew. Chem., Int. Ed. Engl. 1997, 36, 1881-1884). LC(Cond. I): RT=1.273 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₅₀N₈O₆:763.39. found 763.94.

Example M132 methyl((1S)-2-((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-L-alanyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-1-methyl-2-oxoethyl)carbamate

Example M132 Step a

To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (10 g, 87 mmol)in CH₂Cl₂ (50 mL) was added tert-butylchlorodiphenylsilane (25.6 g, 93mmol), triethylamine (12.1 mL, 87 mmol) and DMAP (1.06 g, 8.7 mmol). Themixture was stirred at room temperature for 5 hours, treated with CH₂Cl₂(50 mL) and washed with water (50 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude product waspurified with a flash chromatography (30 to 100% of EtOAc/hexanes) toafford ether M132a as colorless oil (22.7 g, 74% yield). ¹H NMR(DMSO-d₆, δ=2.50, 400 MHz): 7.69 (br s, 1H), 7.64-7.61 (m, 4H),7.50-7.42 (m, 6H), 3.67-3.62 (m, 1H), 3.58-3.51 (m, 2H), 2.24-2.04 (m,3H), 1.89-1.78 (m, 1H), 1.00 (s, 9H).

Example M132 Step b

Di-tert-butyl dicarbonate (28.0 g, 128 mmol) was added slowly to acooled (ice/water) CH₂Cl₂ (120 mL) solution of ether M132a (22.7 g, 64.2mmol), triethylamine (8.95 mL, 64.2 mmol), and DMAP (7.84 g, 64.2 mmol).At the end of addition, the cooling bath was removed and stirringcontinued at ambient condition for 20 hours. The volatile component wasremoved in vacuo, and the crude material was submitted to a flashchromatography (20 to 50% EtOAc/hexanes) to afford carbamate M132b asoff-white solid (29 g, 99% yield). ¹H NMR (DMSO-d₆, δ=2.50, 400 MHz):7.61-7.54 (m, 4H), 7.50-7.38 (m, 6H), 4.19-4.16 (m, 1H), 3.90 (dd,J=10.4, 3.6, 1H), 3.68 (dd, J=10.4, 2.1, 1H), 2.68-2.58 (m, 1H),2.40-2.33 (m, 1H), 2.22-2.12 (m, 1H), 2.01-1.96 (m, 1H), 1.35 (s, 9H),0.97 (s, 9H).

Example M132 Step c

A three-necked flask equipped with a thermometer and a nitrogen inletwas charged with carbamate M132b (10.054 g, 22.16 mmol) and toluene (36mL), and lowered into −55° C. cooling bath. When the internaltemperature of the mixture reached ˜−50° C., Superhydride (23 mL of 1.0M in THF, 23.00 mmol) was added dropwise over 30 minutes whilemaintaining the internal temperature between −50 and −45° C., andstirred for 35 minutes while maintaining the temperature between −50 and−45° C. Hunig's Base (16.5 mL, 94 mmol) was added dropwise over 10minutes. Then DMAP (34 mg, 0.278 mmol) was added in one batch, followedby the addition of trifluoroacetic anhydride (3.6 mL, 25.5 mmol) over 15minutes, while maintaining the internal temperature between −50 and −45°C. The bath was removed 10 minutes later, and the reaction mixture wasstirred for 14 hours while allowing it to thaw to ambient temperature.It was then diluted with toluene (15 mL), cooled with ice-water bath,and treated slowly with water (55 mL) over 5 minutes. At the end ofaddition, the phases were separated, and the organic layer was washedwith water (50 mL, 2×) and then concentrated in vacuo. The crudematerial was purified with a flash chromatography (5% EtOAc/hexanes) toafford carbamate M132c as a colorless viscous oil (7.947 g, 82%). ¹H NMR(DMSO-d₆, δ=2.50, 400 MHz): 7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47(br m, 1H), 5.07-5.01 (br m, 1H), 4.18 (br m, 1H), 3.89 (br m, 0.48H),3.69 (br m, 1.52H), 2.90-2.60 (br m, 2H), 1.40/1.26 (two overlapping s,9H), 0.98 (s, 9H).

Example M132 Step d

Diethylzinc (19 mL of ˜1.1 M in toluene, 20.90 mmol) was added dropwiseover 15 minutes to a cooled (−30° C.) toluene (27 mL) solution ofcarbamate M132c (3.94 g, 9.0 mmol). Then chloroiodomethane (97%,stabilized over copper; 3 mL, 41.2 mmol) was added dropwise over 10minutes, and stirred while maintaining the bath temperature around −25°C. for 1 hour and around −21° C. for 18.5 hours. The reaction was thenopened to air and quenched by a slow addition of 50% saturated NaHCO₃solution (40 mL), and then removed from the cooling bath and stirred atambient condition for 20 minutes. It was filtered through a filter paperand the white cake was washed with 50 mL of toluene. The organic phaseof the filtrate was separated, and washed with water (40 mL, 2×), dried(MgSO₄), filtered, and concentrated in vacuo. The resulting crudematerial was purified with a Biotage system (350 g silica gel; samplewas loaded with 7% EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes) toafford methanopyrrolidine M132d as a colorless viscous oil, mainly asthe trans isomer (3.691 g, 90.7%). [Note: the exact trans/cis ratio hasnot been determined yet at this stage]. ¹H NMR (DMSO-d₆, δ=2.50, 400MHz) of M132d-i: 7.62-7.60 (m, 4H), 7.49-7.40 (m, 6H), 3.76 (br m, 1H),3.67 (br m, 2H), 3.11-3.07 (m, 1H), 2.23 (br m, 1H), 2.03 (br m, 1H),1.56-1.50 (m, 1H), 1.33 (br s, 9H), 1.00 (s, 9H), 0.80-0.75 (m, 1H),0.30 (br m, 1H).

Example M132 Step e

TBAF (7.27 mL of 1.0 M in THF, 7.27 mmol) was added dropwise over 5minutes to a THF (30 mL) solution of the ether M132d (3.13 g, 6.93 mmol)and the mixture was stirred at ambient condition for 4.75 hours. Afterit was treated with saturated NH₄Cl solution (5 mL), most of thevolatile component was removed in vacuo, and the residue was partitionedbetween CH₂Cl₂ (70 mL) and 50% saturated NH₄Cl solution (30 mL). Theaqueous phase was extracted with CH₂Cl₂ (30 mL), and the combinedorganic phase was dried (MgSO₄), filtered, concentrated in vacuo, andthen exposed to high vacuum overnight. The resulting crude material waspurified with a Biotage (40-50% EtOAc/hexanes) to afford alcohol M132eas colorless oil, mainly as the trans isomer, contaminated with tracesof lower Rf impurities (1.39 g, 94%). [Note: the exact trans/cis ratiohas not been determined yet at this stage]. ¹H NMR (DMSO-d₆, δ=2.50, 400MHz) of M132e-i: 4.70 (app t, J=5.7, 1H), 3.62-3.56 (m, 1H), 3.49-3.44(m, 1H), 3.33-3.27 (m, 1H), 3.08-3.04 (m, 1H), 2.07 (br m, 1H),1.93-1.87 (m, 1H), 1.51-144 (m, 1H), 1.40 (s, 9H), 0.76-0.71 (m, 1H),0.26 (br m, 1H).

Example M132 Step f

A semi-solution of NaIO₄ (6.46 g, 30.2 mmol) in H₂O (31 mL) was added toCH₃CN (20 mL) and CCl₄ (20 mL) solution of alcohol M132e (2.15 g, 10.08mmol) prepared above, and RuCl₃ (0.044 g, 0.212 mmol) was addedimmediately and the heterogeneous reaction mixture was vigorouslystirred for 75 minutes. The reaction mixture was diluted H₂O (60 mL) andextracted with CH₂Cl₂ (50 mL, 3×). The combined organic phase wastreated with 1 mL CH₃OH, allowed to stand for about 5 minutes, and thenfiltered through a pad of diatomaceous earth (Celite®). The pad waswashed with CH₂Cl₂ (50 mL), and the filtrate was rotervaped to afford alight charcoal-colored solid. ¹H NMR of the crude material indicated a1.00:0.04:0.18 mole ratio among trans acid M132f-i: presumed cis acidM132f-ii: side product M132f-iii. The crude material was dissolved inEtOAc (˜10 mL) with heating, and allowed to stand at ambient conditionwith seeding. About 15 minutes into the cooling phase, a rapid crystalformation was observed. About 1 hour later, hexanes (˜6 mL) was addedand the mixture was refrigerated overnight (it does not appear thatadditional compound has precipitated out). The mixture was filtered andwashed with ice/water cooled hexanes/EtOAc (2:1 ratio; 20 mL) and driedunder high vacuum to afford the first crop of acid M132f-i (off-whitecrystals, 1.222 g). The mother liquor was rotervaped, and the residuewas dissolved in ˜3 ml of EtOAc (with heating), allowed to stand atambient condition for 1 hour, and then 3 mL hexanes was added and storedin a refrigerator for ˜15 hours. A second crop of acid M132f-i (greycrystals, 0.133 g) was retrieved similarly. ¹H NMR (DMSO-d₆, δ=2.50, 400MHz): 12.46 (br s, 1H), 3.88 (br m, 1H), 3.27 (br m, 1H; partiallyoverlapped with the signal of water), 2.28 (br m, 1H), 2.08 (br m, 1H),1.56 (br m, 1H), 1.40/1.34 (two overlapped br s, 9H), 0.73-0.68 (m, 1H),0.46-0.43 (m, 1H). Optical rotation (10 mg/mL of CHCl₃): [α]_(D)=−216for first crop & −212 for the second crop.

Example M132 Step g

Ketoester M132g was prepared from acid M132f-i and1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) by employing the proceduredescribed for the preparation of ketoester M122a. LC (Cond. I): RT=2.09minutes. LC/MS: Anal. Calcd. for [M+H-Boc]⁺ C₃₃H₃₇N₂O₈: 589.26. found589.29.

Example M132 Step h

Carbamate M132h was prepared from ketoester M132g according to theprocedure described for the preparation of imidazole 1b from ketoamidela, with the exception that 20 mol equiv of NH₄OAc was employed for thethermal cyclization, and that CH₂Cl₂ was employed during the work upstep. LC (Cond. I): RT=1.48 minutes. LC/MS: Anal. Calcd. for [M+H]⁺C₃₈H₄₅N₆O₄: 649.35. found 649.40.

Example M132 Step i

Pyrrolidine M132i (0.4HCl) was prepared from carbamate M132h accordingto the procedure described for the preparation of pyrrolidine M122c. Thecrude material was submitted to subsequent acylation step withoutpurification. ¹H NMR (DMSO-d₆, δ=2.50, 400 MHz): 10.5-10.0 (br signal,not integratable), 8.02 (s, 2H), 7.95 (d, J=8.6, 4H), 7.85 (d, J=8.3,4H), 4.75 (m, 2H), 3.43 (m, 2H), 2.67-2.50 (m, 4H), 1.95 (m, 2H), 1.11(m, 2H), 0.86 (m, 2H). RT=1.00 minutes. LC/MS: Anal. Calcd. for [M+H]⁺C28H20N6: 449.25. found 49.27.

Example M132

Example M132, along with its analogs Example M133-M137 highlighted inthe table below, were prepared as TFA salts from pyrrolidine M132i(0.4HCl) by employing the procedure described for the synthesis ofExample M122 and appropriate acids. Example M132: LC (Cond. I): RT=1.14min; >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₃N₈O₆:707.33. found 707.43.

    Ex- am- ple         Compound Name

RT (LC- Cond.); % homogeneity index; MS data M133 dimethyl(4,4′-biphenyldiyl- bis(1H- imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2- diyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate

1.22 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₇N₈O₆: 735.36; found 735.48 M134 methyl (2-((1R,3S,5R)-3-(4-(4′-(2- ((1R,3S,5R)-2- (((methoxycarbonyl) amino)acetyl)-2-azabicyclo[3.1.0]hex- 3-yl)-1H- imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2-yl)-2- oxoethyl)carbamate

1.12 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₆H₃₉N₈O₆: 679.30; found 679.38 M135 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2- diyl((1S)-1-cyclopropyl- 2-oxo-2,1-ethanediyl)))biscarbamate

1.25 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₄₇N₈O₆: 759.36; found 759.45 M136 methyl ((1R)-1- (((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2R)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2- azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2-yl)carbonyl)-2- methylpropyl)carbamate

1.34 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₅₀N₈O₆: 763.39; found 763.46 M137 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2- diyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

1.38 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₈H₄₇N₈O₆: 831.36; found 831.37

Example M138 methyl((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-acetyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

Example M138 Step a

To a slurry of pyrrolidine M132i (0.4HCl) (0.3 g, 0.32 mmol) in DMF (4mL), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (97 mg, 0.55mmol) and i-Pr₂EtN (0.26 mL, 1.5 mmol) were added. After the mixturebecame a clear solution, HATU (0.2 g, 0.53 mmol) was added, and it wasstirred at room temperature for 3 hours. The volatile component wasremoved in vacuo, and the resulting residue (which was a mixture ofstarting material, and mono- and bis-acylated products) was dissolved inmethanol and purified with a reverse phase HPLC (CH₃OH/H₂O/TFA) toisolate the TFA salt of pyrrolidine M138a as white foam (80 mg). LC(Cond. I): RT=1.17 minutes. LC/MS: Anal. Calcd. for [M+H]⁺ C₃₅H₄₀N₇O₃:606.32. found 606.36.

Example M138

Acetic acid (7.6 mg, 0.13 mmol), i-Pr₂EtN (32 mg, 0.25 mmol), and HATU(53 mg, 0.14 mmol) were sequentially added to a DMF (2 mL) solution ofthe TFA salt of pyrrolidine M138a (40 mg, 0.04 mmol), and the reactionmixture was stirred at room temperature for 3 hours. The volatilecomponent was removed in vacuo, and the residue was dissolved inmethanol and purified with a reverse phase HPLC (CH₃OH/H₂O/TFA) toafford the TFA salt of Example M138 as white foam (8 mg). LC (Cond. I):RT=1.20 min; >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺C₃₇H₄₂N₇O₄: 648.33. found 648.36.

Example M139 methyl((1S)-2-methyl-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl-2-methylpropyl)carbamate

HATU (53 mg) was added to a mixture of the TFA salt of pyrrolidine M138a(40 mg, 0.042 mmol), d-Biotin (10.3 mg, 0.042 mmol) and i-Pr₂EtN (0.044mL, 0.253 mmol), and the reaction mixture was stirred at roomtemperature for 3 hours. The volatile component was removed in vacuo,and the residue was dissolved in methanol and purified with a reversephase HPLC (CH₃OH/H₂O/TFA) to afford the TFA salt of Example M139 as alight yellow solid (7 mg). LC (Cond. I): RT=1.28 min; >95% homogeneityindex. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₅H₅₄N₉O₅S: 832.40. found 832.34.

Example M140N-((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2S)-2-acetamido-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)acetamide

Example M140 Step a

HATU (852 mg, 2.24 mmol) was added to a DMF (20 mL) solution ofpyrrolidine M132i (0.4HCL) (650 mg, 1.09 mmol), Boc-L-Valine (523 mg,2.41 mmol), i-Pr₂EtN (1.15 mL, 6.56 mmol), and the reaction mixture wasstirred at room temperature for 1 hour. The volatile component wasremoved in vacuo, and the crude was dissolved in CH₃OH and purified witha reverse phase HPLC (CH₃OH/H₂O/TFA) to afford 0.96 g of acylatedproduct. A portion of the product (0.72 g) was dissolved in CH₂Cl₂ (4mL), treated with TFA (0.26 mL, 3.35 mmol), and the resulting mixturewas stirred at ambient condition for 4 hours. The volatile component wasremoved in vacuo to afford the TFA salt of M140a-ii, tert-butyl((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate,which was used in the next step without purification. LC (Cond. I):RT=0.93 minutes. LC/MS: Anal. Calcd. for [M+H]⁺ C₃₈H₄₇N₈O₂: 647.38.found 647.26.

The free base form of carbamate M140a-i could be isolated at thecoupling stage as follows: the HPLC fraction was neutralized with excess2.0 N NH₃/CH₃OH, the volatile component was removed in vacuo and theresidue was partitioned between CH₂Cl₂ and ˜5% saturated NaHCO₃solution. The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo to afford M140a-i,(2S)-1-((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2S)-2-amino-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-3-methyl-1-oxo-2-butanamine,as a light yellow foam. LC (Cond. I): RT=1.64 min; >95% homogeneityindex. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₈H₆₃N₈O₆: 847.49. found 847.54.

Example M140

Acetic anhydride (21 mg, 0.204 mmol) and i-Pr₂EtN (0.083 mL, 0.476 mmol)were sequentially added to a DMF (3 mL) solution of the TFA salt ofM140a-ii (75 mg, 0.068 mmol), and the reaction mixture was stirred atambient condition until completion, as determined by LC/MS analysis. Thevolatile component was removed in vacuo, and the residue was dissolvedin CH₃OH and submitted to a reverse phase HPLC (CH₃OH/H₂O/TFA) to affordthe TFA salt of Example M140 as white foam (35 mg). LC (Cond. I):RT=1.18 min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺C₄₂H₅₁N₈O₄: 731.40. found 731.34.

Example M141N-((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2S)-2-((cyclopropylcarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)cyclopropanecarbamate

Example M141 was prepared as a TFA salt from amine M140a-ii (TFA salt)and cyclopropanecarboxylic acid according to the coupling proceduredescribed for the synthesis of carbamate M140a-i. LC (Cond. I): RT=1.33min; >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₆H₅₅N₈O₄:783.42. found 783.36.

Example M142-M143

Example M142 (free base) and Example M143 (TFA salt) were prepared byemploying the procedures described for the synthesis of Example M140 andappropriate materials.

    Ex- am- ple         Compound Name

RT (LC- Cond.); % homogeneity index; MS data M142 tert-butyl ((1R)-1-(((1R,3S,5R)-3-(4-(4′- (2-((1R,3S,5R)-2- ((2R)-2-((tert)-butoxycarbonyl) amino)- 3-methylbutanoyl)-2- azabicyclo[3.1.0] hex-3-yl)-1H-imidazol-4-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-2-azabicyclo[3.1.0]hex- 2-yl)carbonyl)-2- methylpropyl) carbamate

1.65 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₈H₆₃N₈O₆: 847.49; found 847.54 M143 N-((1R)-1- (((1R,3S,5R)-3-(4-(4′-(2- ((1R,3S,5R)- 2-((2R)-2- acetamido-3- methylbutanoyl)-2-azabicyclo[3.1.0] hex-3- yl)-1H-imidazol- 4-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 2-azabicyclo[3.1.0] hex-2- yl)carbonyl)-2- methylpropyl)acetamide

1.26 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₅₁N₈O₄: 731.40; found 731.34

Example M144N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))di(2-pyrimidinamine)

A mixture of the TFA salt of amine M140a-ii (75 mg, 0.068 mmol),2-bromopyrimidine (32.4 mg, 0.204 mmol), and i-Pr₂EtN (0.048 mL, 0.272mmol) in DMSO (0.2 mL)/toluene (1.2 mL) was heated at 90° C. for 20hours. Additional 2-bromopyrimidine (32.4 mg, 0.204 mmol) was added andheating continued for 8 hours. Most of the volatile component wasremoved in vacuo and the residue was purified twice by a reverse phaseHPLC system, (CH₃OH/H₂O/TFA) followed by (ACN/H₂O/TFA), to afford theTFA salt of Example M144, contaminated with unknown minor impurities, asa yellow foam (10 mg). RT=20.9 minutes (see the LC method detailbelow); >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺C₄₆H₅₁N₁₂O: 803.43. found 803.70.

Method Details for Analysis of Example M144:

Instrument: Waters Acquity HPLC with Waters PDA UV-Vis detection andWaters SQ MS (ESCI probe)

Column: Waters Acquity BEH C18; 1.7 um; 150×2.1 mm ID; (at 35 C)

Mobile phase A: Water/acetonitrile (97.5/2.5) with 5 mM ammoniumformate;

0.05% formic acid at pH 3.3

Mobile phase B: Acetonitrile/Water (97.5/2.5) with 5 mM ammoniumformate;

0.05% formic acid

Flow: 0.35 ml/min

Hold 10% B 0-1 min

10-35% B 1-20 min

35-98% B 20-32 min

hold 98% 32-35 min

98-10% B 35-35.5 min

hold 10% B 35.5-40.0 min

UV detection: @260 nm

Example M145 methyl((1S)-1-(((6S)-6-(4-(4′-(2-((6S)-5-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)carbonyl)-2-methylpropyl)carbamate

Example M145 Step a

TMSCHN₂ (3.63 mL of 2.0 M/ether, 7.26 mmol) was added dropwise to aCH₃OH (33 mL)/benzene (33 mL) solution of(S)-1-tert-butyl4-methylenepyrrolidine-1,2-dicarboxylate (1.5 g, 6.60 mmol), and thereaction mixture was stirred at ambient condition for 3.5 hours. Removalof the volatile component in vacuo afforded ester M145a as a tan oil(1.57 g). ¹H NMR (CDCl₃, δ=7.26 ppm, 500 MHz): 5.01-4.98 (m, 2H),4.50-4.48 (m, 0.5H), 4.39-4.37 (m, 0.5H), 4.07-4.04 (m, 2H), 3.71 (s,3H), 3.01-2.87 (m, 1H), 2.66-2.55 (m, 1H), 1.46/1.41 (two overlapping s,9H).

Example M145 Step b

Diethylzinc (5.65 mL of 1.1 M in toluene, 6.22 mmol) was added dropwiseover 20 minutes to a cooled (−22° C.) toluene (4 mL) solution of esterM145a (0.50 g, 2.07 mmol). Cloroiodomethane (0.90 mL, 12.4 mmol) wasadded dropwise over 10 minutes, and the reaction mixture was stirred at−22° C. for 18 hours. The reaction was quenched with saturated solutionof NaHCO₃ (aq.) (5 mL) at similar temperature and was then allowed tothaw to ambient temperature. The mixture was filtered, and theprecipitate was washed with EtOAc (100 mL). The layers of the filtratewere separated, and the organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting crude material was purified with aBiotage (10-20% EtOAc/hexanes) to afford ester M145b as colorless oil(0.139 g). ¹H NMR (CDCl₃, δ=7.26 ppm, 500 MHz): 4.47-4.44 (m, 0.5H),4.47-4.34 (m, 0.5H), 3.73 (s, 3H), 3.39-3.27 (m, 2H), 2.25-2.18 (m, 1H),1.86-1.84 (m, 0.5H), 1.78-1.75 (m, 0.5H), 1.44/1.40 (two overlapping s,9H), 0.63-0.48 (m, 4H). LC (Cond. II): RT=2.26 minutes. LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₂H₁₉NNaO₄: 264.12. found 264.22.

Example M145 Step c

A water (0.61 mL) solution of LiOH (0.016 g, 0.65 mmol) was added to anethanol (1.2 mL) solution of ester M145b (0.139 g, 0.544 mmol), and thereaction mixture was stirred at ambient condition for 19 hours. Thevolatile component was removed in vacuo, and the residue was dissolvedin water (5 mL), cooled (ice/water), acidified to a pH region of 3.0with 1N HCl (aq.), and then extracted with EtOAc (50 mL, 3×). Thecombined organic layer was dried (MgSO₄), filtered, and concentrated invacuo to afford acid M145c as viscous oil which solidified upon standing(0.129 g). ¹H NMR (CDCl₃, δ=7.26 ppm, 500 MHz): 4.48-4.40 (m, 1H),3.55-3.05 (m, 2H), 2.37-1.87 (m, 2H), 1.47/1.44 (two overlapping s, 9H),0.78-0.50 (m, 4H). LC (Cond. II): RT=2.26 minutes. LC/MS: Anal. Calcd.for [M+Na]⁺ C₁₂H₁₉NNaO₄: 264.12. found 264.22.

Example M145 Step d

Carbamate M145d was prepared starting from acid M145c and1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) and employing the generalprocedure described for the synthesis of M122b with the exception thatthe ketoester-cyclization step was conducted under microwave conditions(140° C.; 90 min). LC (Cond. II): RT=2.54 minutes. LC/MS: Anal. Calcd.for [M+H]⁺ C₄₀H₄₉N₆O₄: 677.38. found 677.45.

Example M145 Step e

25% TFA/CH₂Cl₂ (5.3 mL) was added to carbamate M145d (0.718 g, 1.06mmol) and the resultant mixture was stirred at ambient condition for 5hours. The volatile component was removed in vacuo, and the residue wasfree-based with MCX (6 g, CH₃OH washing; 1:1 CHCl₃/2 N NH₃/CH₃OHelution) to afford pyrrolidine M145e as a light yellow solid (406 mg).¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 11.89 (br s, 2H), 7.82 (d, J=7.9,4H), 7.67 (d, J=7.9, 4H), 7.50 (br s, 2H), 4.37 (m, 2H), 2.92 (app d,J=9.8, 2H), 2.81 (app d, J=10.1, 2H), 2.09-2.05 (m, 2H), 1.98-1.94 (m,2H), 0.62-0.49 (m, 8H). LC (Cond. II): RT=1.75 minutes. LC/MS: Anal.Calcd. for [M+H]⁺ C₃₀H₃₃N₆: 477.28. found 477.35.

Example M145

Example M145, along with its analogs Example M146-M147 highlighted inthe table below, were prepared as TFA salts starting from pyrrolidineM145 and appropriate acids, by employing the general HATU couplingcondition outlined for Example-1, with the exception that the reactionmixture was diluted with CH₃OH and directly submitted to a reverse phaseHPLC (CH₃OH/H₂O/TFA) purification. Example M145: LC (Cond. II), RT=2.27min); >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺=C₄₄H₅₅N₈O₆:791.42. found 791.44.

        Example         Compound Name

RT (LC- Cond.); % homogeneity index; MS data M146 methyl(2-((6S)-6-(4-(4′-(2-((6S)- 5- (((methoxycarbonyl)amino)acetyl)-5-azaspiro[2.4]hept-6-yl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5- azaspiro[2.4]hept-5-yl)-2- oxoethyl)carbamate

1.97 minutes (Cond. II); >95%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₃N₈O₆: 707.33; found 707.36 M147 methyl ((1S)-2-((6S)-6-(4-(4′-(2-((6S)-5-(N- (methoxycarbonyl)-L- alanyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-4-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-1-methyl- 2-oxoethyl)carbamate

2.01 minutes (Cond. II); >95%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₄₇N₈O₆: 735.36; found 735.41 M148 dimethyl (4,4′-biphenyldiylbis(1H-imidazol-4,2-diyl(6S)-5- azaspiro[2.4]heptane-6,5- diyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate

2.14 minutes (Cond. II); >95%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₅₁N₈O₆: 763.39; found 763.46 M149 methyl ((1R)-1-(((6S)-6-(4-(4′-(2-((6S)-5-((2R)-2- ((methoxycarbonyl)amino)-3- methylbutanoyl)-5-azaspiro[2.4]hept-6-yl)- 1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5- azaspiro[2.4]hept-5-yl)carbonyl)-2-methylpropyl)carbamate

2.44 minutes (Cond. II); >95%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₅₅N₈O₆: 791.42; found 791.44 M150 dimethyl (4,4′-biphenyldiylbis(1H-imidazol-4,2-diyl(6S)-5- azaspiro[2.4]heptane-6,5-diyl((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate

2.52 minutes (Cond. II); >95%; LC/MS: Anal. Calcd. for [M + H]⁺C₅₀H₅₁N₈O₆: 859.39; found 859.42

Example M151 methyl((1S)-1-(((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example M151 Step a

The title compound was synthesized according to a literature protocol(J. Med. Chem., 2006, 49, 3520) with the following purificationmodifications: the crude material (2.7 g) was recrystallized fromEtOAc/hexanes at ambient temperature to afford acid M151a as a whitecrystal (2.2 g). ¹H NMR (CDCl₃, δ=7.24 ppm, 400 MHz): 4.32 (br m, 1H),3.89 (br m, 1H), 2.40 (br m, 1H), 2.00 (m, 2H), 1.65 (m, 1H), 1.45 (s,9H), 1.20 (d, J=5.6, 3H). LC (Cond. I): RT=1.40 minutes. LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₁H₂₀NO₄Na: 252.12. found 252.21.

Example M151 Step b

To a mixture of acid M151a and1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) (1.85 g, 4.66 mmol) inacetonitrile (50 mL), i-Pr₂EtN (1.24 g, 9.6 mmol) was added dropwise,and the reaction was stirred at room temperature for 7 hr. The volatilecomponent was removed in vacuo and the residue was partitioned betweenethyl acetate and water (1:1, 100 mL). The organic layer was separatedand washed with saturated NaHCO₃ and brine, dried (Na₂SO₄), filtered,and concentrated in vacuo to afford ketoester M151b as white foam (3.19g), which was used in the next step without purification. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 400 MHz): 8.10 (d, J=8.5, 4H), 7.95 (d, J=8.5, 4H),5.70-5.50 (br m, 4H), 4.40 (br m, 2H), 3.90 (br m, 2H), 2.25 (m, 2H),2.15 (m, 4H), 1.60 (m, 2H), 1.41 (s, 8H), 1.39 (s, 10H), 1.20 (m, 6H).LC (Cond. I): RT=2.15 minutes. LC/MS: parent ion was not observed.

Example M151 Step c

A mixture of ketoester M151b (2.94 g, 4.24 mmol) and ammonium acetate(6.54 g, 85 mmol) in xylene (40 mL) was heated in a sealed tube at 140°C. for 2 hours. The volatile component was removed in vacuo and theresidue was partitioned between CH₂Cl₂ (100 mL) and water (50 mL). Theorganic layer was washed with saturated NaHCO₃ (20 mL), dried (Na₂SO₄),concentrated in vacuo. The resultant crude material was purified with aBiotage (0-100% EtOAc/hexanes) to afford imidazole M151c as light brownsolid (1.72 g). LC (Cond. I): RT=1.03 minutes. LC/MS: Anal. Calcd. for[M+H]⁺ C₃₈H₄₉N₆O₄: 653.37. found 653.40.

Example M151 Step d

4 N HCl in dioxane (14 mL, 56 mmol) was added dropwise to a dioxane (70mL) solution of carbamate M151c (1.72 g, 2.63 mmol), and the reactionmixture was stirred at room temperature for 4 hours. Removal of thevolatile component in vacuo afforded the HCl salt of pyrrolidine M151das a yellow solid (1.58 g). ¹HNMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 9.85(br s, 1H), 8.80 (br s, 1H), 7.89 (d, J=8.3, 4H), 7.77 (s, 2H), 7.75 (d,J=8.6, 4H), 4.70 (br m, 2H), 3.75 (br m, 2H), 2.45-2.35 (m, 4H), 2.25(m, 2H), 1.75 (m, 2H), 1.50 (d, J=6.6, 6H). LC (Cond. I): RT=1.03minutes. LC/MS: Anal. Calcd. for [M+H]⁺ C₂₈H₃₃N₆: 453.28. found 453.28.

Example M151

Example M151, along with its analogs Example M152-M161 highlighted inthe table below, were prepared as TFA salts starting from pyrrolidineM151d and appropriate acids, by employing the general HATU couplingcondition outlined for Example-1, with the exception that the reactionmixture was diluted with CH₃OH and directly submitted to a reverse phaseHPLC purification (CH₃OH/H₂O/TFA). Example M151: LC (Cond. I): RT=1.41min; >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H₅₅N₈O₆:767.42. found 767.40.

        Example         Compound Name

RT (LC- Cond.); % homogeneity index; MS data M152 methyl((1R)-1-(((2S,5S)-2-(4-(4′- (2-((2S,5S)-1-((2R)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

1.38 minutes (Cond. I); >98% LC/MS: Anal. Calcd. for [M + H]⁺C₄₂H₅₅N₈O₆: 767.42; found 767.33 M153 dimethyl (4,4′-biphenyldiylbis(1H-imidazol-4,2-diyl((2S,5S)-5- methyl-2,1-pyrrolidinediyl)((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate

1.46 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₈H₅₁N₈O₆: 835.39; found 835.31 M154 dimethyl (4,4′-biphenyldiylbis(1H-imidazol-4,2-diyl((2S,5S)-5- methyl-2,1-pyrrolidinediyl)((2S)-1-oxo-1,2- butanediyl)))biscarbamate

1.27 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₅₁N₈O₆: 739.39; found 739.28 M155 methyl (2-((2S,5S)-2-(4-(4′-(2-((2S,5S)-1- (((methoxycarbonyl)amino)acetyl)-5-methyl-2-pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1- pyrrolidinyl)-2- oxoethyl)carbamate

1.19 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₆H₄₃N₈O₆: 683.33; found 683.32 M156 methyl (2-((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-(2- ((methoxycarbonyl)amino)-2- methylpropanoyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-1,1,- dimethyl-2- oxoethyl)carbamate

1.33 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₀H₅₁N₈O₆: 739.39; found 739.28 M157 methyl ((1S)-2-((2S,5S)-2-(4-(4′-(2-((2S,5S)-1-(N- (methoxycarbonyl)-L-alanyl)-5-methyl-2-pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-5-methyl-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

1.21 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₇N₈O₆: 711.36; found 711.23 M158 4,4′-(4,4′-biphenyldiyl)bis(2-((2S,5S)-5-methyl-1-(3- methylbutanoyl)-2-pyrrolidinyl)- 1H-imidazole)

1.42 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₉N₆O₂: 621.39; found 621.28 M159 4,4′-(4,4′-biphenyldiyl)bis(2-((2S,5S)-5-methyl-1- (phenylacetyl)-2-pyrrolidinyl)-1H- imidazole)

1.46 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₄₄H₄₅N₆O₂: 689.36; found 689.26 M160 (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-4,2- diyl((2S,5S)-5-methyl-2,1-pyrrolidinediyl)))bis(3-methyl-1- oxo-2-butanol)

1.27 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₉N₆O₄: 653.38; found 653.27 M161 (2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-4,2- diyl((2S,5S)-5-methyl-2,1-pyrrolidinediyl)))bis(3-methyl-1- oxo-2-butanol)

1.267 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for [M + H]⁺C₃₈H₄₉N₆O₄: 653.38; found 653.34

Example M1622-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-4-(4′-(2-((2S,5S)-1-acetyl-5-methyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole

Acetic anhydride (38.4 mg, 0.376 mmol) and i-Pr₂EtN (0.153 mL, 0.877mmol) were added to a DMF (3 mL) solution of the HCl salt of pyrrolidineM151d (75 mg, 0.125 mmol), and the mixture was stirred at roomtemperature for 2 hours. The volatile component was removed in vacuo,and the residue was dissolved in CH₃OH and purified with a reverse phaseHPLC (CH₃OH/H₂O/TFA) to afford the TFA salt of M162 as a white foam (55mg). LC (Cond. I): RT=1.13 min; >95% homogeneity index. LC/MS: Anal.Calcd. for [M+H]⁺ C₃₂H₃₇N₆O₂: 537.30. found 537.21.

Examples J1-J14.f and E1-E5m

LCMS conditions 1: Phenomenex-Luna 4.6×50 mm S10, 0 to 100% B over 2min, 3 min stop time, 4 mL/min, 220 nm, A: 10% CH₃OH—90% H2O—0.1% TFA;B: 90% CH₃OH—10% H2O—0.1% TFA.

LCMS conditions 2: Phenomenex-Luna 4.6×50 mm S10, 0 to 100% B over 3min, 4 min stop time, 4 mL/min, 220 nm, A: 10% CH₃OH—90% H2O—0.1% TFA;B: 90% CH₃OH—10% H2O—0.1% TFA.

LCMS conditions 3: Luna 4.6×30 mm C18, 0 to 100% B over 2 min, 3 minstop time, 5 mL/min, 220 nm, A: 5% Acetonitrile-90% H2O—10 Mm NH₄OAc; B:90% Acetonitrile −10% H2O—0.1% 10 Mm NH₄OAc.

Reference: J. Org. Chem. (1992) 57, 1784.

108 mL of (1,3-dioxan-2-ylethyl) magnesium bromide (0.5M) was added to asolution of 4-bromobenzaldehyde (10 g, 54.0 mmol) in THF (350 mL) at−78° C. under nitrogen and stirred for 2 hours before warming to 0° C.The reaction was quenched with sat NH₄Cl soln, diluted with diethylether and washed with brine. The crude product was charged (CH₂Cl₂) to a40M Biotage silica gel cartridge; Gradient elution 15-100% B over 750 mL(A=Hexanes; B=ethyl acetate) to give Example J1,1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-ol (quantitative yield).¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz,2H), 4.70-4.66 (m, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.12-4.19 (m, 2H), 3.76(tt, J=11.9, 2.7 Hz, 2H), 2.87 (d, J=3.7 Hz, 1H), 2.12-2.03 (m, 1H),1.86-1.87 (m, 2H), 1.74-1.68 (m, 2H), 1.36-1.32 (m, 1H). RT=1.8 minutes(condition 1); LRMS: No parent ion evident.

Reference: JOC (1989) 54 5387.

PCC (8.16 g, 59.8 mmol) was admixed with 9 g SiO₂ and ground (mortar &pestle) and suspended in Dichloromethane (360 mL). To the suspension wasadded in one portion Example J1,1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-ol (9 g, 29.9 mmol)dissolved in 5 mL of the same solvent. The reaction mixture was stirredfor 2 hours an filtered through celite (rinse with (CH₂Cl₂). After beingconcentrated the residue was charged (CH₂Cl₂) to a 40 M Biotage silicagel cartridge. Gradient elution 15-70% B over 750 mL (A=Hexanes; B=ethylacetate) gave Example J2,1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-one 7.7 g (86%). ¹H NMR(500 MHz, CDCl₃) δ 7.84 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 4.65(t, J=4.9 Hz, 1H), 4.09-4.06 (m, 2H), 3.74 (dt, J=11.0, 2.4 Hz, 2H),3.06 (t, J=7.3 Hz, 2H), 2.07-2.01 (m, 3H), 1.35-1.31 (m, 1H). LCMS:RT=1.9 minutes (condition 1); C13H15BrO3 Calcd.: 299. found: 299 (M+H)⁺.

The potassium tert-butoxide (15 mL, 1M in THF) was added dropwise to asolution of 1-(4-bromophenyl)ethanone (3 g, 15.07 mmol) in DMSO (60 mL)at 0° C. and stirred for 30 min under nitrogen. The enolate wascannulated into a solution of 2-(bromomethyl)-1,3-dioxolane (2.52 g,15.07 mmol) in DMSO (10 mL) at 0° C. and the reaction allowed to warm to24° C. and stirred 6 hours. Concentrate to remove solvent (high vacuumrotory evaporation) and charge (CH₂Cl₂) of residue to a 40 (M) Biotagesilica gel cartridge and gradient elution 5-35% B over 1 L (A=Hexanes;B=ethyl acetate) gave Example J2a,1-(4-bromophenyl)-3-(1,3-dioxolan-2-yl)propan-1-one 327 mg (7.6%) and571 mg of a bis addition product. ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d,J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.97 (t, J=4.3 Hz, 1H), 3.96-3.94(m, 2H), 3.87-3.84 (m, 2H), 3.08-3.05 (m, 2H), 2.15-2.11 (m, 2H).

Reference: Bromination JACS (1952) 74 6263. Displacement/Cyclization J.Med. Chem. (2001) 44 2990.

Bromine (1.3 mL, 25.2 mmol) was added to a solution of Example J2,1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-one (7.7 g, 25.7 mmol) indiethyl ether (60 mL) and 1,4-dioxane (40 mL) and the solution stirred30 min at 24° C. (Until TLC indicated reaction complete). The solventwas removed by rotory evaporation and the residue was taken up inacetonitrile (350 mL). (S)—N-Boc-Proline (5.54 g, 25.7 mmol) was addedfollowed by dropwise addition of Hunig's base (8.5 mL, 51.5 mmol) andthe reaction was stirred 6 hours before being concentrated. The crudeproduct was taken up in CH₂Cl₂ and charged to a 40 (M) Biotage silicagel cartridge. Gradient elution 15-100% B over 1 L (A=hexanes; B=ethylacetate) gave Example J3,2-(1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)-1-oxopropan-2-yl) 1-tert-butylpyrrolidine-1,2-dicarboxylate 13 g (100%).). RT=2.2 minutes (condition1); LCMS: Anal. C23H30BrNO7 Calcd. 534. found: 534 (M+Na)⁺.

Ammonium acetate (6.45 g, 107 mmol) was added to a solution of ExampleJ3, 2-(1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)-1-oxopropan-2-yl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (5.5 g, 10.7 mmol) in xylene(120 mL) and stirred for 3 hours at 130° C. in a screw capped 500 mLpressure vessel. After being cooled, the reaction mixture was dilutedwith ethyl acetate (600 mL) and washed with sat NaHCO₃ and brine beforebeing concentrated by rotory evaporation under high vacuum. The crudeproduct was taken up in CH₂Cl₂ and charged to a 40 (M) Biotage silicagel cartridge. Gradient elution 15-100% B over 2 L (A=CH₂Cl₂; B=ethylacetate) gave Example J4, (S)-tert-butyl2-(4-((1,3-dioxan-2-yl)methyl)-5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate2.22 g (40%). ¹H NMR (500 MHz, CDCl₃) δ 7.46 (s, 4H), 4.94-4.92 (m, 1H),4.77 (t, J=4.9 Hz, 1H), 4.15-4.12 (m, 2H), 3.81-3.75 (m, 2H), 3.3-3.37(m, 2H), 3.0-2.90 (m, 2H), 2.10-2.05 (m, 4H), 1.94-1.91 (m, 1H), 1.49(s, 9H) 1.36-1.34 (m, 1H). RT=1.8 minutes (condition 1); HRMS: Anal.C23H30BrN3O4 Calcd. 492.1492. found: 492.1505 (M+H)⁺.

J4a Derived from example J2a

RT = 1.68 min, (Cond 1) HRMS: Anal. Calcd. for C₂₂H₂₉BrN₃O₄ 478.1336;found: 478.1356 (M + H)⁺.

Benzyl bromide (9.98 g, 58.3 mmol) was added to a solution of4-(4-bromophenyl)-4-oxobutanoic acid (15.0 g, 58.3 mmol) and K₂CO₃ (3.5g, 58.3 mmol) in DMF (300 mL) and stirred for 18 hours. The reactionmixture was partitioned between water (200 mL) and ethyl acetate (500mL). Sat'd NaHCO₃ soln (20 mL) was added and the aqueous layer extractedwith ethyl acetate (2×) and the combined organic layers were washed withbrine and dried and filtered. Concentration gave Example J5, benzyl4-(4-bromophenyl)-4-oxobutanoate 16 g (79%) which was used withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.6 Hz, 2H),7.61 (d, J=8.5 Hz, 2H), 7.35-7.34 (m, 5H), 5.14 (s, 2H), 3.27 (t, J=6.7Hz, 2H), 2.81 (t, J=6.7 Hz, 2H). HRMS: Anal. C17H16BrNO3 Calcd.347.0277. found: 347.0283 (M+H)⁺.

Bromine (2.5 mL, 46.1 mmol) was added to a solution of Example J5,benzyl 4-(4-bromophenyl)-4-oxobutanoate (16 g, 46.1 mmol) in ether (200mL) and 1,4-Dioxane (50 mL) and the solution was stirred for 6 hoursbefore being concentrated by rotory evaporation and taken up inacetonitrile (450 mL). Sodium azide (3.0 g, 46.1 mmol) was added and thereaction mixture stirred 18 hours. The solvent was removed uponconcentration and the residue taken up in ethyl acetate and wash withwater, brine, dried Na₂SO₄, and filtered. Concentration gave benzyl3-azido-4-(4-bromophenyl)-4-oxobutanoate 17 g (95%) which was carriedforward without further purification. Tin (II) chloride dehydrate (24.9g, 131 mmol) was added to a solution of benzyl3-azido-4-(4-bromophenyl)-4-oxobutanoate (17 g, 43.8 mmol) in CH₃OH (550mL) and stirred for 14 hours at 65° C. The reaction was concentrated byrotory evaporation and dried under high vacuum for 18 hours to give amixture of benzyl and Example J6, methyl3-amino-4-(4-bromophenyl)-4-oxobutanoate, (transesterification hadoccurred) and carried forward with purification. RT=1.3 minutes(condition 1); LCMS: Anal. C11H12BrNO3 Calcd. 286.0. found: 286.14(M+H)⁺.

HATU (10.5 g, 27.6 mmol) was added to a solution of Example J6, methyl3-amino-4-(4-bromophenyl)-4-oxobutanoate (10 g, 27.6 mmol),(S)—N-Boc-proline (7.13 g, 33.1 mmol), and Hunig's Base (45 mL, 276mmol) in DMF (150 mL) and stirred for 18 hours at 24° C. The reactionwas diluted with ethyl acetate (2 vol) and H2O (¼ vol) and sat NaHCO₃ (⅛vol). Filter through diatomaceous earth (Celite®) to remove tin salts.Extract aqueous layer (2×) with ethyl acetate, and concentrate combinedorganic to remove solvents (high vacuum on rotory evaporator). Theresidue was subject to a short silica gel chromatography to removeby-products, and the resultant crude product was charged (CH₂Cl₂) a 65(M) Biotage silica gel cartridge. Gradient elution 15-70% B over 2 L(A=Hexanes; B=ethyl acetate) gave a less polar band of (2S)-tert-butyl2-(4-(benzyloxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate1.35 g (8.7%) and more polar Example J7, (2S)-tert-butyl2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate7.6 g (49%). RT=2.0 minutes (condition 1); LCMS: Anal. C21H27BrN2O6Calcd. 383. found: 383 (M-Boc).

Ammonium acetate (9.4 g, 157 mmol) was added to a solution of ExampleJ7, (2S)-tert-butyl2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate(7.6 g, 15.7 mmol) in xylene (80 mL) and stirred for 4 hours at 140° C.in a screw capped 150 mL pressure vessel. After being cooled, thereaction mixture was diluted with ethyl acetate and washed with satNaHCO₃ and brine before being concentrated by rotory evaporation underhigh vacuum. The crude product was taken up in CH₂Cl₂ and charged to a40 (M) Biotage silica gel cartridge. Gradient elution 15-100% B over 2 L(A=CH₂Cl₂; B=ethyl acetate) gave Example J8, (S)-tert-butyl2-(4-(4-bromophenyl)-5-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate3.38 g (46%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.54 (s, 4H), 4.83-4.73 (m,1H), 3.81 (br. s, 1H), 3.62 (s, 3H), 3.53-3.51 (m, 1H), 3.38-3.31 (m,2H), 2.25-2.15 (m, 1H), 1.99-1.83 (m, 3H), 1.41/1.16 (s, 9H). RT=1.6minutes (Condition 1). LCMS: Anal. Calcd. for C21H26BrN3O4 464.11.found: 464.40 (M+H)⁺.

Reference: J. Med. Chem. (84), 27, 20. Syn. Lett. (2004) 2315.

The conc. HCl (40 mL) was added dropwise to a solution of1-(4-bromophenyl)pentan-1-one (4.68 g, 19.41 mmol) and sodium nitrite(4.02 g, 58.2 mmol) in THF (80 ml) at 0° C. and allowed to warm to roomtemperature and stirred 18 hours. The reaction mixture was diluted withdiethyl ether and the organic phase washed with sat'd NaHCO₃ and brine.Concentration gave (Z)-1-(4-bromophenyl)-2-(hydroxyimino)pentan-1-one3.1 g (33%) as an oil which was used without further purification.).RT=2.1 min, (Condition 1) LCMS: Anal. Calcd. for C11H12BrN1O2 270.01.found: 270.15 (M+H)⁺.

Reference: Bioorg. Med. Chem. Lett (2002) 1009.

The 28% ammonium hydroxide (15 mL) was added to a solution of(Z)-1-(4-bromophenyl)-2-(hydroxyimino)pentan-1-one (1.5 g, 5.55 mmol)and (S)—N—BOC-prolinal (1.1 g, 5.55 mmol) in methanol (60 mL) andstirred for 18 hours at 24° C. The reaction mixture was partitionedbetween CH₂Cl₂ and water and the organic phase concentrated and applied(CH₂Cl₂) to a 40 (M) Biotage silica gel column. Gradient elution,5-100%, over 1 L (A=Hexanes; B=ethyl acetate) gave (S)-tert-butyl2-(4-(4-bromophenyl)hydroxy-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(863 mg, 34.5% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 7.54 (m, 4H),5.0-4.88 (m, 1H), 3.53-3.41 (m, 1H), 3.41-3.36 (m, 1H), 2.72 (t, J=7.0Hz, 2H), 2.24-2.03 (m, 2H), 1.96-1.91 (m, 1H), 1.89-1.81 (m, 1H), 1.60(h, J=7.6 Hz, 2H), 1.39/1.17 (s, 9H). 0.92 (t, J=7.0 Hz, 3H). RT=1.9min, (Condition 1) LCMS: Anal. Calcd. for C₂₁H₂₈BrN₃O₃ 450.13. found:450.33 (M+H)⁺.

Reference: Chem. Pharm. Bull (1994) 42, 560.

The triethyl phosphite (0.9 mL, 5.33 mmol) was added to a solution of(S)-tert-butyl2-(4-(4-bromophenyl)hydroxy-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(800 mg, 1.776 mmol) in DMF (2 mL) and stirred for 18 hours at 80° C.Add second 0.8 mL and the reaction was continued an additional 8 hours,cooled, and taken up in ethyl acetate (400 mL) and washed with water andbrine. Apply in CH₂Cl₂ to a 25 (M) Biotage silica gel column. Gradientelution, 15-100%, over 750 mL (A=Hexanes; B=ethyl acetate) gave(S)-tert-butyl2-(4-(4-bromophenyl)-5-propyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate585 mg (76%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.55-7.53 (m, 4H), 4.80-4.69(m, 1H), 3.53-3.51 (m, 1H), 3.38-3.32 (m, 1H), 2.71 (t, J=7.0 Hz, 2H),2.24-2.11 (m, 1H), 2.0-1.79 (m, 1H), 1.89-1.79 (m, 2H), 1.63-1.59 (m,2H), 1.41/1.17 (s, 9H). 0.91 (t, J=7.6 Hz, 3H). RT=1.8 min,(Condition 1) LRMS: Anal. Calcd. for C₂₁H₂₈BrN₃O₂ 434.14. found: 434.0(M+H)⁺.

To a mixture of 2,4′-dibromopropiophenone (4.96 g, 0.017 mol) andN-Boc-L-proline (4.09 g, 0.019 mol) in dry CH₃CN (75 mL) was added DIEA(3.30 mL, 0.019 mol) and the mixture was stirred at room temperatureunder Ar for 16 hours. The mixture was then concentrated under reducedpressure and the concentrate was partitioned with CH₂Cl₂-10% saturatedNaHCO₃. The organic phase was washed (brine), dried (Na₂SO₄), filtered,and concentrated to give the proline ester (7.28 g, >100%) as acolorless gum which was used as such in the next step. LCMS: Anal.Calcd. for C19H24BrNO5: 426. found: 426 (M+H)⁺.

A mixture of the proline ester (0.435 g, 1.0 mmol) and ammonium acetate(0.308 g, 4.0 mmol) in toluene (5 mL) was heated at 140° C. (bathtemperature) in a sealed tube for 5 hours. The cooled reaction mixturewas evaporated and the residue was chromatographed (SiO₂/ethylacetate-hexane, 3:2) to give Example E1 (0.320 g, 79%) as a nearlycolorless foam. ¹HNMR (400 MHz, CDCl₃) δ 7.53 (s, 4H), 4.98 (m, 0.3H),4.87 (m, 0.7H), 3.65 (m, 1H), 3.4-3.6 (m, 1H), 2.50 (s, 3H), 2.32 (m,1H), 2.13 (m, 2H), 1.94 (m, 1H), 1.47 (s, 3H), 1.31 (s, 6H). LCMS: Anal.Calcd. for C19H24BrN3O2: 405, 407. found: 406, 408 (M+H)⁺.

E1a

RT = 1.71 min (condition 1); LCMS: Anal. Calcd. for C₁₈H₂₃BrN₃O₂:392.10; found 391.96 [M + H]+ E1b

RT = 2.27 min, (Cond 2) LRMS: Anal. Calcd. for C₁₈H₂₂BrFN₃O₂ 410.09 and412.09; found 410.08 and 412.08 (M + H)⁺. E1c

RT = 2.19 min, (Cond 2) LCMS: Anal. Calcd. for C₁₈H₂₁BrF₂N₃O₂ 428.08 and430.08; found: 428.07 and 430.07 (M + H)⁺.

A mixture of Example E1, (S)-tert-butyl2-(4-(4-bromophenyl)-5-methyl-1H-imidazol-2-yl)-pyrrolidine-1-carboxylate(1.568 g, 3.86 mmol), bis(pinacolato)diboron (2.058 g, 8.10 mmol) andpotassium acetate (0.947 g, 9.65 mmol) in dioxane (25 mL) was purgedwith a stream of Ar bubbles for 10 min and then (Ph₃P)₄Pd (0.223 g, 0.19mmol) was added and purging with Ar was continued for another 10 min.The reaction vessel was then sealed and heated at 80° C. (bathtemperature) for 18 hours. The cooled mixture was diluted withdichloromethane and then it was washed (H₂O, brine), dried (Na₂SO₄),filtered, and concentrated. The residue was triturated with ethylacetate and the resulting solid was filtered, washed with a little ethylacetate and dried in vacuo to give the title compound (quantitative) asa solid. It was used as such in the next step without furtherpurification. ¹HNMR (400 MHz, DMSO-d₆) δ 11.93 (br s, 0.3H), 11.71 (brs, 0.7H), 7.65 (br s, 4H), 4.79 (m, 0.4H), 4.69 (m, 0.6H), 3.52 (m, 1H),3.36 (m, 2H), 2.38 (s, 3H), 1.78-2.26 (m, 4H), 1.41 (s, 4H), 1.30 (s,10H), 1.17 (m, 6H). LCMS: Anal. Calcd. for C25H36BN3O4: 453. found: 454(M+H)⁺.

E2a

RT = 1.64 min (condi 1); LCMS: Anal. Calcd. for C24H35BN3O4: 440.27;found 440.23. [M + H]+ E2b

RT = 2.44 min, (Cond 2) LCMS: Anal. Calcd. for C24H33BF2N3O4: 476.25;found: 476.51 [M + H]⁺.

A mixture of Example E1, (S)-tert-butyl2-(4-(4-bromophenyl)-5-methyl-1H-imidazol-2-yl)-pyrrolidine-1-carboxylate(0.682 g, 1.68 mmol), Example E2a, (S)-tert-butyl2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.764 g, 1.74 mmol) and NaHCO₃ (0.465 g, 5.53 mmol) in a mixture of DME(20 mL) and H₂O (5 mL) was purged with a stream of Ar bubbles for 10min. To this mixture was added (Ph₃P)₄Pd (0.091 g, 0.08 mmol) andpurging with Ar was continued for another 10 min. The reaction vesselwas then sealed and heated at 80° C. (bath temperature) for 18 hours.The cooled mixture was concentrated under reduced pressure and theconcentrate was diluted with ethyl acetate and washed with H₂O. Theaqueous phase was back-extracted with ethyl acetate and the combinedorganic phase was washed (brine), dried (Na₂SO₄), filtered, andconcentrated to give a gum. The residue was chromatographed (SiO₂/ethylacetate-hexane, 7:3) to give Example E3 (0.592 g, 59%) as a foam. ¹HNMR(400 MHz, CDCl₃) δ 7.37-7.88 (m, 8H), 7.27 (s, 1H), 5.10 (t, J=7.65 Hz,2H), 3.45 (m, 4H), 3.00 (m, 2H), 2.44 (s, 3H), 2.20 (br s, 4H), 1.99 (m,2H), 1.53 (s, 18H). LCMS: Anal. Calcd. for C37H46N6O4: 638. found: 639(M+H)⁺.

E3a Derived from example E2 and E3

LCMS: Anal. Calcd. for C38H48N6O4: 652; found: 653 (M + H)⁺. J12 Derivedfrom example E2a and J4 tert-butyl (2S)-2-(4-(4′- (2-((2S)-1-(tert-butoxycarbonyl)-2- pyrrolidinyl)-4-(1,3- dioxan-2-ylmethyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinecarboxylate

RT = 1.65 min, (cond 3) HRMS: Anal. Calcd. for C₄₁H₅₃N₆O₆ 725.4021;found: 725.4026 (M + H)⁺. J12a Derived from example E2a and J4atert-butyl (2S)-2-(4-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2-pyrrolidinyl)-4-(1,3- dioxolan-2-ylmethyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate

RT = 1.62 min, (cond 1) HRMS: Anal. Calcd. for C₄₀H₅₁N₆O₆ 711.3865;found: 711.3874 (M + H)⁺. J12b Derived from example E2a and J8tert-butyl (2S)-2-(4-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-5-(2-methoxy-2-oxoethyl)- 1H-imidazol-2-yl)-1- pyrrolidinecarboxylate

RT = 1.72 min, (cond 1) HRMS: Anal. Calcd. for C₃₉H₄₈N₆O₆ 697.3087;found: 697.3721 (M + H)⁺. J12c Derived from example E2a and J11tert-butyl (2S)-2-(4-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-5-propyl-1H-imidazol-2-yl)-1- pyrrolidinecarboxylate

RT = 1.72 min, (cond 1) LCMS: Anal. Calcd. for C₃₉H₅₀N₆O₄ 667.40; found:667.30 (M + H)⁺. J12d ethyl 2-((2S)-1-(tert- butoxycarbonyl)-2-pyrrolidinyl)-5-(4′-(2- ((2S)-1-(tert- butoxycarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4-carboxylate

RT = 1.70 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C38H47N6O6 683.36;found: 683.42 (M + H)⁺ J12e Derived from example E2b and E1b tert-butyl(2S)-2-(4-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-4,4-difluoro-1- pyrrolidinecarboxylate

RT = 2.24 min, (cond 2) LCMS: Anal. Calcd. for C₃₆H₄₂F₃N₆O₄ 679.32;found: 679.57 (M + H)⁺.

The LAH (0.7 mL, 1M in THF) was added to a solution of Example J12d,(466 mg, 0.669 mmol) in THF (50 mL) and stirred at 0° C. for 1.5 hoursbefore slowly allowing to warm to room temperature. After 3 hours thereaction was quenched with water (0.4 mL), 15% NaOH (0.4 mL) and water(0.4 mL) and the aluminum salts removed by filtration. The salts wererinsed with THF, the combined filtrates were concentrated, and theresidue charged (CH₂Cl₂) to a 25 (S) Biotage silica gel cartridge andgradient eluted 15-100% over 1 L solvent (A=CH₂Cl₂; B=10% CH₃OH/ethylacetate) to give Example J12f, tert-butyl(2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-4-(hydroxymethyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate,88 mg (20%) in addition to recovered J12d and over reduction. RT=1.7minutes (Condition 1); LCMS Anal. Calcd. for C37H46N6O5 665.36. found:665.46 (M+H)⁺.

A solution of Example E3 (0.240 g, 0.376 mmol) in 5 mL of TFA-CH₂Cl₂(4:1) was stirred at room temperature for 2 hours and then the volatileswere removed under reduced pressure. The resulting gum was taken up in aminimum volume of CH₃OH and adsorbed on an MCX LP cartridge (6 g,pre-conditioned with CH₃OH). The cartridge was washed with CH₃OH andthen eluted with 2M NH₃ in CH₃OH. The product-containing fractions werecombined and evaporated to give E4 (quantitative) as a gum which wasused as such in the next step. LCMS: Anal. Calcd. for C27H30N6: 438.found: 439 (M+H)⁺.

E4a

LCMS: Anal. Calcd. for C₂₈H₃₂N₆: 452; found: 453 (M + H)⁺. J13 Derivedfrom example J12

RT = 1.18 min, (cond 1) LCMS: Anal. Calcd. for C₃₁H₃₆N₆O₂ 525.29; found:525.31 (M + H)⁺. Prepared using experi- mental conditions from example152k-1. J13a Derived from example J12a

RT = 1.14 min, (cond 1) LCMS: Anal. Calcd. for C₃₀H₃₆N₆O₂ 513.29; found:513.42 (M + H)⁺. Prepared using experi- mental conditions in example152k-1. J13b Derived from example J12b

RT = 1.19 min, (cond 1) LCMS: Anal. Calcd. for C₂₉H₃₂N₆O₂ 497.26; found:497.48 (M + H)⁺. Prepared using experi- mental conditions as outlined inexample 152k-1. J13c Derived from example J12c

RT = 1.26 min, (cond 1) LCMS: Anal. Calcd. for C₃₉H₅₀N₆O₄ 467.28; found:467.55 (M + H)⁺. Prepared using experi- mental conditions from example152k-1. J13e Derived from example J12e 2-((2S)-4,4- difluoro-2-pyrrolidinyl)-4- (3′-fluoro-4′-(2- ((2S)-2- pyrrolidinyl)-1H-imidazol-4- yl)-4- biphenylyl)-1H- imidazole

RT = 1.77 min, (Cond 2) LCMS: Anal. Calcd. for C₂₆H₂₆F₃N6₈ 479.22;found: 479.39 (M + H)⁺. Prepared using experi- mental conditions fromexample 152k-1. J13f Derived from example J12f

RT = 1.02 min, (cond 1) LCMS: Anal. Calcd. for C₂₇H₃₀N₆O 455.25; found:455.47 (M + H)⁺. Prepared using experi- mental conditions from example152k-1.

A solution of (R)-2-(dimethylamino)-2-phenylacetic acid hydrochloride(0.047 g, 0.220 mmol), HATU (0.084 g, 0.220 mmol) and DIEA (0.17 mL,0.70 mmol) in dry DMF (1 mL) was stirred at room temperature for 5 minand then a solution of E4 (0.041 g, 0.094 mmol) in dry DMF (0.5 mL) wasadded. The mixture was stirred at room temperature for 18 hours and thenit was quenched with AcOH (0.2 mL) and a few drops of TFA. This solutionwas submitted directly to preparative HPLC (C-18/CH₃CN—H2O+0.1% TFA) togive the TFA salt of Example E5,(1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-5-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine(0.011 g, 10%) as a white solid. ¹HNMR (400 MHz, CH₃OH-d₄) δ 7.80-7.93(m, 6H), 7.71-7.74 (m, 2H), 7.50-7.67 (m, 10H), 5.37-5.51 (m, 2H), 5.30(m, 2H), 4.04 (br s, 3H), 3.00-3.13 (m, 4H), 2.81 (br s, 8H), 2.55 (s,2H), 2.49 (s, 1H), 2.36 (m, 2H), 2.12-2.25 (m, 5H), 1.96 (br s, 2H).LCMS: Anal. Calcd. for C47H52N8O2: 760. found: 761 (M+H)⁺.

E5a Derived from example E4 (1R)-2-((2S)-2-(4- (4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-5- methyl-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N-diethyl-2-oxo-1- phenylethanamine

LCMS: Anal. Calcd. for C₅₁H₆₀N₈O₂: 816; found: 817 (M + H)⁺. E5b Derivedfrom example E4 1-((1R)-2-((2S)-2- (4-(4′-(4-methyl-2- ((2S)-1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-phenylethyl)piperi- dine

LCMS: Anal. Calcd. for C₅₃H₆₀N₈O₂: 840; found: 841 (M + H)⁺. E5c Derivedfrom example E4 methyl ((1R)-2- ((2S)-2-(4-(4′-(2- ((2S)-1-((2R)-2-((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-5- methyl-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1- phenylethyl)car- bamate

LCMS: Anal. Calcd. for C₄₇H₄₈N₈O₆: 820; found: 821 (M + H)⁺. E5d Derivedfrom example E4 methyl ((1S)-2- ((2S)-2-(4-(4′-(2- ((2S)-1-(N-(methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-4- methyl-1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C₃₇H₄₄N₈O₆: 696; found: 697 (M + H)⁺. E5e Derivedfrom example E4 methyl ((1S)-1- (((2S)-2-(4-(4′-(2- ((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-5- methyl-1H- imidazol-2-yl)-1-pyrrolidinyl)car- bonyl)-2-methyl- propyl)car- bamate

LCMS: Anal. Calcd. for C₄₁H₅₂N₈O₆: 752; found: 753 (M + H)⁺. E5f Derivedfrom example E4 methyl ((1S,2R)-2- methoxy-1-(((2S)-2-(4-(4′-(2-((2S)-1- (N- methoxycarbonyl)- O-methyl-L- threonyl)-2-pyrrolidinyl)-4- methyl-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)car- bonyl)propyl)car- bamate

LCMS: Anal. Calcd. for C₄₁H₅₂N₈O₈: 784; found: 785 (M + H)⁺. E5g Derivedfrom example E4a (1R,1′R)-2,2′-(4,4′- biphenyldiylbis((4- methyl-1H-imidazole-5,2- diyl)(2S)-2,1- pyrrolidinediyl))bis (N,N-dimethyl-2-oxo-1- phenylethanamine)

LCMS: Anal. Calcd. for C₄₈H₅₄N₈O₂: 774; found: 775 (M + H)⁺. E5h Derivedfrom example E4a (1R,1′R)-2,2′-(4,4′- biphenyldiylbis((4- methyl-1H-imidazole-5,2- diyl)(2S)-2,1- pyrrolidinediyl))bis (N,N-diethyl-2-oxo-1- phenylethanamine)

LCMS: Anal. Calcd. for C₅₂H₆₂N₈O₂: 830; found: 831 (M + H)⁺. E5i Derivedfrom example E4a 1,1′-(4,4′- biphenyldiylbis((4- methyl-1H-imidazole-5,2- diyl)(2S)-2,1- pyrrolidine- diyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl)))dipi- peridine

LCMS: Anal. Calcd. for C54H62N8O2: 854: found: 855 (M + H)⁺. E5j Derivedfrom example E4a dimethyl (4,4′- biphenyldiylbis((4- methyl-1H-imidazole-5,2- diyl)(2S)-2,1- pyrrolidine- diyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl)))bis- carbamate

LCMS: Anal. Calcd. for C48H50N8O6: 834; found: 835 (M + H)⁺. E5k Derivedfrom example E4a methyl ((1S)-2- ((2S)-2-(4-(4′-(2- ((2S)-1-(N-(methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-5- methyl-1H-imidazol-4-yl)-4- biphenylyl)-5- methyl-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

LCMS: Anal. Calcd. for C38H46N8O6: 710; found: 711 (M + H)⁺. E5l Derivedfrom example E4a methyl ((1S)-1- (((2S)-2-(4-(4′-(2- ((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-4-methyl-1H- imidazol-5-yl)-4- biphenylyl)-5- methyl-1H- imidazol-2-yl)-1-pyrrolidinyl)car- bonyl)-2-methyl- propyl)carbamate

LCMS: Anal. Calcd. for C42H54N8O6: 766; found: 767 (M + H)⁺. E5m Derivedfrom example E4a methyl ((1S,2R)-2- methoxy-1-(((2S)-2-(4-(4′-(2-((2S)-1- (N- (methoxycarbonyl)- O-methyl-L- threonyl)-2-pyrrolidinyl)-5- methyl-1H- imidazol-4-yl)-4- biphenylyl)-5- methyl-1H-imidazol-2-yl)-1- pyrrolidinyl)car- bonyl)propyl)car- bamate

LCMS: Anal. Calcd. for C42H54N8O8: 798; found: 799 (M + H)⁺. J14 Derivedfrom example J13 methyl ((1S)-1- (((2S)-2-(4-(1,3- dioxan-2-ylmethyl)-5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl) car- bonyl)-2-methyl- propyl)carbamate

RT = 1.37 min, (Cond 1); HRMS: Anal. Calcd. for C₄₅H₅₈N₈O₈ 839.4450;found: 839.4456 (M + H)⁺. J14a Derived from example J13a methyl((1S,2R)-1- (((2S)-2-(4-(2,2- dimethoxyethyl)-5- (4′-(2-((2S)-1-(N-(methoxycarbonyl)- O-methyl-L- threonyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)car-bonyl)-2-methoxy- propyl)carbamate

RT = 1.44 min, (Cond 1); HRMS: Anal. Calcd. for C₄₄H₅₈N₈O₁₀ 859.4349;found: 859.4352 (M + H)⁺. J14a.1 Derived from example J13a methyl((1S)-1- (((2S)-2-(4-(2,2- dimethoxyethyl)-5- (4′-(2-((2S)-1- ((2S)-2-((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)car-bonyl)-2-methyl- propyl)carbamate

RT = 1.44 min, (Cond 1); HRMS: Anal. Calcd. for C₄₄H₅₈N₈O₈ 827.4450;found: 827.4449 (M + H)⁺. J14b Derived from example J13b methyl(2-((2S)-1- (N- (methoxycarbonyl)- O-methyl-L- threonyl)-2-pyrrolidinyl)-4-(4′- (2-((2S)-1-(N- (methoxycarbonyl)- O-methyl-L-threonyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H-imidazol-5- yl)acetate

HRMS: Anal. Calcd. for C₄₃H₅₄N₈O₁₀ 843.4036; found: 843.4046 (M + H)⁺.J14b.1 Derived from example J13b methyl (2-((2S)-1- (N-(methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-4-(4′- (2-((2S)-1-(N-(methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H- imidazol-5- yl)acetate

RT = 1.42 min, (Cond 1); HRMS: Anal. Calcd. for C₄₃H₅₄N₈O₈ 811.4137;found: 811.4154 (M + H)⁺. J14c Derived from example J13c methyl ((1S)-2-((2S)-2-(4-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2-pyrrolidinyl)-4- propyl-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate

RT = 1.42 min, (Cond 1); HRMS: Anal. Calcd. for C₃₉H₄₉N₈O₆ 725.3775;found: 725.3758 (M + H)⁺. J14c.1 Derived from example J13c(1R)-2-((2S)-2-(4- (4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-5-propyl-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- diethyl-2-oxo-1-phenylethanamine

RT = 1.39 min, (Cond 1); HRMS: Anal. Calcd. for C₅₃H₆₅N₈O₂ 845.5225;found: 845.5207 (M + H)⁺. J14c.2 Derived from example J13c methyl((1S)-1- (((2S)-2-(4-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl)amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-5- propyl-1H- imidazol-2-yl)-1- pyrrolidinyl)car-bonyl)-2-methyl- propyl)carbamate

RT = 1.59 min, (Cond 1); HRMS: Anal. Calcd. for C₄₃H₅₇N₈O₆ 781.4317;found: 781.4377 (M + H)⁺. J14e Derived from example J13e methyl ((1S)-1-(((2S)-4,4-difluoro- 2-(4-(3′-fluoro-4′- (2-((2S)-1-((2S)-2-((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)car-bonyl)-2-methyl- propyl)carbamate

RT = 1.99 min, (Cond 2) HRMS: Anal. Calcd. for C₄₀H₄₈F₃N₈O₆ 793.3643;found: 793.3653 (M + H)⁺. J14e.1 Derived from example J13e(1R)-2-((2S)-2-(4- (4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2-phenylacetyl)-4,4- difluoro-2- pyrroldinyl)-1H- imidazol-4-yl)-3-fluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N-diethyl-2-oxo-1- phenylethanamine

RT = 1.79 min, (Cond 2) HRMS: Anal. Calcd. for C₅₀H₅₆F₃N₈O₂ 857.4473;found: 857.4478 (M + H)⁺. J14f Derived from example J13f methyl ((1S)-1-(((2S)-2-(4- (hydroxymethyl)-5- (4′-(2-((2S)-1- ((2S)-2-((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)car-bonyl)-2-methyl- propyl)carbamate

RT = 1.40 min, (Cond 1); HRMS: Anal. Calcd. for C₄₁H₅₃N₈O₇ 769.4037;found: 769.4020 (M + H)⁺. J14f.1 Derived from example J13f methyl((1S)-2- ((2S)-2-(4-(4′-(4- (hydroxymethyl)-2- ((2S)-1-(N-(methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate

RT = 1.21 min, (Cond 1); HRMS: Anal. Calcd. for C₃₇H₄₅N₈O₇ 713.3411;found: 713.3391 (M + H)⁺.Section PY

Example PY1 4,4′-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyltrifluoroacetic acid salt

To a solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(2.61 g, 4.18 mmol) in CH₂Cl₂ (25 mL) was added TFA (12 mL) and themixture was allowed to stir at room temperature. After allowing thereaction to stir for 2 hours it was concentrated to dryness in vacuo.The material was used without further purification in subsequent steps.LCMS: Anal. Calcd. for C₂₆H₂₈N₆: 424. found: 425 (M+H)⁺.

Example PY2(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-3-methylbutan-1-one)

To a solution of4,4′-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyltetrakis(2,2,2-trifluoroacetate) (2.695 g, 3.06 mmol),(S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1.60 g, 7.34mmol) and DIEA (5.3 mL, 30.6 mmol) in DMF (15 mL) was added HATU (2.39g, 6.27 mmol) and the mixture was allowed to stir at room temperaturefor 14 h. MeOH (5 mL) was added and the mixture was allowed to stir for4 h. It was then poured into ca. 150 mL of cold water and allowed tostand for 20 min. The solid was filtered and dried under vacuumovernight and then purified by biotage (40+M, 0 to 25% MeOH in EtOAc) togive a yellow brown foam (1.76 g, 70%). ¹HNMR (300 MHz, DMSO-d₆) δ12.11-12.17 (m, 1H), 11.76 (s, 1H), 7.73-7.94 (m, 4H), 7.62-7.70 (m,4H), 7.49 (d, J=1.8 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.06 (dd, J=2.7,6.3 Hz, 2H), 4.00-4.07 (m, 2H), 3.77 (s, br, 3H), 2.07-2.15 (m, 4H),1.88-2.00 (m, 6H), 1.37 (s, 18H), 0.88 (d, J=6.6 Hz, 6H), 0.82 (d, J=6.6Hz, 6H). LCMS: Anal. Calcd. for C₄₆H₆₂N₈O₆: 822. found: 823 (M+H)⁺. Thematerial was suspended in CH₂Cl₂ (15 mL) and TFA (6 mL) was added. Afterstirring for 2 h the solvents were removed in vacuo giving a yelloworange solid. The solid was partitioned between sat NaHCO₃ and EtOAchowever the material was insoluble in EtOAc. Therefore the volatileswere removed in vacuo and the residue was loaded on to an SCX cationexchange cartridge and eluted with MeOH and then NH₃ in MeOH (2M). Theappropriate fractions were concentrated in vacuo to give a yellow foam(1.24 g, 65%). LCMS: Anal. Calcd. for C₃₆H₄₆N₈O₂: 622. found: 623(M+H)⁺. The material was used as is in subsequent steps.

The following were prepared similarly. Note that in some cases the TFAsalt obtained from the Boc deprotection was carried forward directly.

Analytical Example Structure Data Example PY3

LCMS: Anal. Calcd. for C₃₆H₄₂N₈O₂: 618; found: 619 (M + H)⁺. Example PY4

LCMS: Anal. Calcd. for C₃₂H₃₈N₈O₂: 566; found: 567 (M + H)⁺. Example PY5

LCMS: Anal. Calcd. for C₃₄H₄₂N₈O₂: 594; found: 595 (M + H)⁺. Example PY6

LCMS: Anal. Calcd. for C₃₄H₄₂N₈O₄: 626; found: 627 (M + H)⁺. Example PY7

LCMS: Anal. Calcd. for C₃₆H₄₂N₈O₂: 618; found: 619 (M + H)⁺.

Example PY8(N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))di(2-pyrimidinamine)

A mixture of(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-3-methylbutan-1-one)(222 mg, 0.36 mmol), 2-bromopyrimidine (0.170 g, 1.07 mmol) and iPr₂NEt(0.25 mL, 1.432 mmol) in toluene (3 mL) and DMSO (0.5 mL) was heated at90° C. overnight. LCMS indicated the reaction to be incomplete thereforeheating was continued for a further 12 hours. The volatiles were removedin vacuo and the residue was diluted with MeOH and purified by prep HPLC(CH₃CN—H₂O—NH₄OAc). The appropriate fractions were concentrated in vacuoand subsequently re-purified by prep HPLC (CH₃CN—H₂O-TFA). Theappropriate fractions were adsorbed onto an MCX cation exchange resincartridge (Oasis) and the resin was washed with MeOH and eluted with 2MNH3 in MeOH. The solvent was removed in vacuo and the residue waslyophilized to give a colorless solid (17.2 mg, 6%). ¹HNMR (300 MHz,DMSO-d₆) δ 12.15, 12.28 (s, 1H, rotamers, 1:1 ratio), 8.28 (d, J=4.8 Hz,4H), 7.79 (app d, J=8.1 Hz, 4H), 7.62-7.70 (m, 4H), 7.49 (d, J=1.5 Hz,2H), 6.85 (d, J=8.4 Hz, 2H), 6.60 (t, J=4.8 Hz, 2H), 5.05 (dd, J=6.9,4.0 Hz, 2H), 4.50 (app t, unresolved dd, J=8.5, 8.0 Hz, 2H), 3.98-4.06(m, 2H), 3.78-3.85 (m, 2H), 1.98-2.23 (m, 10H), 0.96 (d, J=6.6 Hz, 6H),0.92 (d, J=6.6 Hz, 6H). LCMS: Anal. Calcd. for C₄₄H₅₀N₁₂O₂: 778. found:779 (M+H)⁺.

The following were prepared similarly:

Note that in some cases the TFA salt obtained from the Boc deprotectionwas carried forward directly and an appropriate amount of iPr₂NEt wasadded to the reaction mixture.

Com- pound Analytical Name Example Structure Data N,N′-(4,4′- biphenyl-diyl bis(1H- imidazole- 4,2-diyl (2S)- 2,1- pyrro- lidinediyl ((1S)-1-cyclo- propyl- 2-oxo-2,1- ethane- diyl))) di(2- pyrimidin- amine)Example PY9

LCMS: Anal. Calcd. for C₃₆H₄₂N₈O₂: 618; found: 619 (M + H)⁺. N,N′-(4,4′-biphenyl- diyl bis(1H- imidazole- 4,2-diyl (2S)- 2,1- pyrroli- dinediyl((2S)-1- oxo-1,2- propane- diyl))) di(2- pyrimi- dine- amine) ExamplePY10

LCMS: Anal. Calcd. for C₃₂H₃₈N₈O₂: 566; found: 567 (M + H)⁺. N,N′-(4,4′-biphenyl- diyl bis(1H- imidazole- 4,2-diyl (2S)- 2,1- pyrroli- dinediyl((2S)-1- oxo-1,2- butane- diyl))) di(2- pyrimidin- amine) Example PY11

LCMS: Anal. Calcd. for C₃₄H₄₂N₈O₂: 594; found: 595 (M + H)⁺. N,N′-(4,4′-biphenyl- diyl bis(1H- imidazole- 4,2-diyl (2S)- 2,1- pyrroli- dinediyl((2S)-3- meth- oxy-1- oxo-1,2- propane- diyl))) di(2- pyrimidin- amine)Example PY12

LCMS: Anal. Calcd. for C₃₄H₄₂N₈O₄: 626; found: 627 (M + H)⁺. N,N′-(4,4′-biphenyl- diyl bis(1H- imidazole- 4,2-diyl (2S)- 2,1- pyrroli- dinediyl((2S, 3R)-3- meth- oxy-1- oxo-1,2- butane- diyl))) di(2- pyrimidin-amine) Example PY13

LCMS: Anal. Calcd. for C₃₆H₄₂N₈O₂: 618; found: 619 (M + H)⁺.

Example PY14 Modified Method

A mixture of(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-3-methylbutan-1-one)(50 mg, 0.080 mmol), 2-chloro-4-methylpyrimidine (103 mg, 0.803 mmol),and DIPEA (0.140 mL, 0.803 mmol) in NMP (3 mL) was heated in a sealedtube for 4 h at 140° C. using a Microwave. The volatiles were removed invacuo and the residue was diluted with MeOH and filtered through aStrata XC MCX cartridge. The cartridge was washed with methanol. Thecompound was release from the cartridge by washing with a solution of 2Mof Ammonia/Methanol. The filtrate was evaporated under reduced pressureto give an orange oil. The crude material was purified HPLC(CH₃CN—H₂O—NH₄OAc). The appropriate fractions were concentrated in vacuoand subsequently re-purified by prep HPLC (CH₃CN—H₂O-TFA). Theappropriate fractions were concentrated in vacuo to give a Yellow solid(21.5 mg, 31.9%). LCMS: Anal. Calcd. for C₄₆H₅₄N₁₂O₂: 807. found: 807.5(M+H)⁺.

Ex- am- ple Structure Analytical Data Ex- am- ple PY15

LCMS: Anal. Calcd. for C₄₆H₄₈F₆N₆O₂: 914; found: 915.16 (M + H)⁺. Ex-am- ple PY16

LCMS: Anal. Calcd. for C₄₈H₅₈N₁₂O₆: 898; found: (M + H)⁺ 899.21. 16 Ex-am- ple PY17

LCMS: Anal. Calcd. for C₄₈H₅₈N₁₂O₂: 834; found: (M + H)⁺ 835.45. Ex- am-ple PY18

LCMS: Anal. Calcd. for C₄₆H₅₄N₁₂O₄S₂: 870; found: (M + H)⁺ 871.24.

Example PY19(S)-2-amino-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methylbutan-1-one

The title compound was prepared from (S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and(S)-2-amino-3-methylbutanoic acid by the procedures detailed in Examples1 and 2. ¹HNMR (300 MHz, DMSO-d₆) δ 11.73 (s, 1H), 7.68 (d, J=5.9 Hz,1H), 7.65 (d, J=5.9 Hz, 1H), 7.46-7.58 (m, 3H), 5.14, 5.05 (dd, J=7.0,3.0 Hz, 1H, rotamers, 1:1 ratio), 3.66 (app t, J=6.5 Hz, 1H), 3.53-3.61and 3.38-3.47 (m, 1H, rotamers, 1:1 ratio), 3.28 (s, 2H), 1.70-2.21 (m,6H), 0.75-0.88 (m, 6H). LCMS: Anal. Calcd. for C₁₈H₂₃BrN₄O: 390, 392.found: 391, 393 (M+H)⁺.

Example PY201-((S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)thiourea

To a solution of(S)-2-amino-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methylbutan-1-one(1.530 g, 3.91 mmol) in CH₂Cl₂ (10 mL) was addedO-(9H-fluoren-9-yl)methyl carbonisothiocyanatidate (1.100 g, 3.91 mmol)as a solid in one portion. The mixture was allowed to stir at roomtemperature for 12 h. Piperidine (2 mL) was added to the mixture and itwas allowed to stir at room temperature for 1 h. A further portion ofpiperidine (2 mL) was added and the solution allowed to stir 1 h. Thesolution was concentrated to dryness and the residue was purified bycolumn chromatography (biotage, eluting with 5:4.5:0.5 hex:EtOAc:MeOH,and then 5% MeOH in EtOAc). The title compound as obtained as a lightyellow glass (1.30 g, 74%). ¹HNMR (300 MHz, DMSO-d₆) δ 11.81 (s, H),7.65 (d, J=8.8 Hz), 7.63-7.71 (m, overlap with previous peak, 2H total),7.42-7.56 (m, 2H), 7.10-7.14 (m, 1H), 5.06 (dd, J=7.0, 3.0 Hz, 1H), 4.94(app t, J=8.0 Hz, 1H), 4.72-4.76 and 4.56-4.62 (m, 1H, rotamers, 1:1ratio), 3.77-3.90 (m, 1H), 2.07-2.14 (m, 2H), 1.90-1.98 (m, 3H), 0.93(d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H). LCMS: Anal. Calcd. forC₁₉H₂₄BrN₅OS: 449, 451. found: 450, 452 (M+H)⁺.

Example PY21(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one

A solution of1-((S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)thiourea(1.29 g, 2.86 mmol) was dissolved in EtOH (50 mL) and2-chloroacetaldehyde (0.4 mL, 3.15 mmol) was added. The mixture washeated at 70° C. overnight. A further portion of 2-chloroacetaldehyde(0.4 mL, 3.15 mmol) was added and heating continued for a further 12 h.The solution was concentrated in vacuo and the residue was purified bycolumn chromatography (biotage), eluting with 50% EtOAc in hexanes andthen 10% MeOH in EtOAc. The desired product was isolated as aorange-brown foam (557.2 mg). LCMS (NH₄OAc) shows this to be ofsufficient purity. Eluting further with 100% MeOH gave a second fraction(980.8 mg) which was shown to contain the product by TLC (5:4.5:0.5hex:EtOAc:MeOH). This second fraction from the column was re-purified togive a light orange-brown foam (426.6 mg). The two fractions werecombined to afford the title compound as a orange brown foam (983.8 mg,72%).

¹HNMR (300 MHz, CD₃OD) δ 7.57 (app d, J=8.0 Hz, 2H), 7.47 (app d, J=8.0Hz, 2H), 7.32 (s, 1H), 6.98 (d, J=3.6 Hz, 1H), 6.55 (d, J=3.6 Hz, 1H),5.32-5.35 and 5.10-5.15 (m, 1H, rotamers, 1:3 ratio), 4.08-4.15 (m, 1H),3.82-3.90 (m, 1H), 3.03-3.15 (m, 1H), 2.03-2.33 (m, 4H), 1.06 and 0.99(d, J=7.0 Hz, 3H, rotamers 1:3 ratio), 1.04 and 0.94 (d, J=7.0 Hz, 3H,rotamers 1:3 ratio). LCMS: Anal. Calcd. for C₂₁H₂₄BrN₅OS: 473, 475.found: 474, 476 (M+H)⁺.

Example PY22(S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one

A mixture of(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one(87.5 mg, 0.184 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (141 mg,0.553 mmol), potassium acetate (91 mg, 0.922 mmol) and Pd(Ph₃P)₄ (21.31mg, 0.018 mmol) was suspended in dioxane and degassed by bubbling N₂through the mixture. It was then heated at 85° C. After heating for 4 hthe mixture was concentrated and purified by passing through a pad ofsilica gel eluting with 1:1 hex:EtOAc, and then EtOAc (neat) to giveafforded the desired product as a light yellow film (101 mg). LCMS(CH₃CN—H₂O—NH₄OAc) showed that the product was contaminated with ca. 10%PPh₃O. The material was used as is in subsequent steps. LCMS: Anal.Calcd. for C₂₇H₃₆BN₅O₃S: 521. found: 522 (M+H)⁺.

Example PY23(N,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))bis(1,3-thiazol-2-amine)

A mixture of(S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one(275 mg, 0.527 mmol),(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one(250 mg, 0.527 mmol), NaHCO₃ (133 mg, 1.582 mmol) and Pd(Ph₃P)₄ (60.9mg, 0.053 mmol) in DME (3 mL) and Water (1 mL) was degassed by passing astream of N₂ through the mixture. The vessel was sealed and the reactionwas heated at 80° C. overnight. The reaction mixture was diluted withH₂O and extracted with EtOAc containing ca. 5% MeOH (×3). The combinedorg layers were concentrated, dissolved in MeOH and loaded onto an MCXcartridge. The cartridge was washed with MeOH and then NH₃ in MeOH (2M).The appropriate fractions were concentrated in vacuo and the residue waspurified by prep HPLC (CH₃CN—H₂O—NH₄OAc). The material was purified bycolumn chromatography (biotage) eluting with 0 to 20% MeOH in EtOAc.Further purification by prep HPLC (CH₃CN—H₂O—NH₄OAc) followed bylyophilization afforded the title compound as a colorless solid (6.9 mg,2%).

¹HNMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 11.75 (s, 2H), 7.75-7.80 (m,4H), 7.68-7.71 (m, 4H), 7.49 (s, 2H), 6.99 (d, J=3.7 Hz, 2H), 6.57 (d,J=3.7 Hz, 2H), 5.34-5.36 (m, 1H), 5.07 (app dd, J=3.7, 7.0 Hz, 2H), 4.42(t, J=8.4 Hz, 2H), 3.98-4.05 (m, 2H), 3.79-3.85 (m, 2H), 3.44-3.56 (m,1H), 1.97-2.21 (m, 8H), 1.01 and 0.95 (d, J=7.0 Hz, 6H, rotamers, 1:3ratio), 0.99 and 0.92 (d, J=7.0 Hz, 6H, rotamers, 1:3 ratio). LCMS:Anal. Calcd. for C₄₂H₄₈N₁₀O₂S₂: 788. found: 789 (M+H)⁺.

Examples FY1-FY3

Examples FY1-FY3 were prepared according to the protocols described forthe synthesis of Example F66 and by employing appropriate materials.

LC/MS Condition:

Column: Phenomenex 10u 3.0×50 mm

Start % B=0

Final % B=100

Gradient Time=3 min

Flow Rate=4 mL/Min

Wavelength=220

Solvent A=10% MeOH—90% H₂O—0.1% TFA

Solvent B=90% MeOH—10% H₂O—0.1% TFA

RT (LC-Cond. is noted above); % Example R homogeneity index; MS data FY1

2.03 min; >95%; LC/MS: Anal. Calcd. for [M + H]⁺ C₃₈H₅₁N₈O₆S₂ 779.34;found: 779.72 FY2

2.19 min; >95%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₅N₈O₆S₂ 807.37;found: 807.78 FY3

2.24 min; >95%; LC/MS: Anal. Calcd. for [M + H]⁺ C₄₂H₅₅N₈O₆S₂ 831.37;found: 832.02

BIOLOGICAL ACTIVITY

An HCV Replion assay was utilized in the present disclosure, and wasprepared, conducted and validated as described in commonly ownedPCT/US2006/022197 and in O'Boyle et. al. Antimicrob Agents Chemother.2005 April; 49(4): 1346-53.

HCV 1b-377-neo replicon cells were used to test the currently describedcompound series as well as cells resistant to compound A due to a Y2065Hmutation in NS5A (described in application PCT/US2006/022197). Thecompounds tested were determined to have more than 10-fold lessinhibitory activity on cells resistant to compound A than wild-typecells indicating a related mechanism of action between the two compoundseries. Thus, the compounds of the present disclosure can be effectiveto inhibit the function of the HCV NS5A protein and are understood to beas effective in combinations as previously described in applicationPCT/US2006/022197 and commonly owned WO/04014852. Further, the compoundsof the present disclosure can be effective against the HCV 1b genotype.It should also be understood that the compounds of the presentdisclosure can inhibit multiple genotypes of HCV. Table 2 shows the EC50values of representative compounds of the present disclosure against theHCV 1b genotype. In one embodiment compounds of the present disclosureare active against the 1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes. EC50ranges against HCV 1b are as follows: A=1-10 μM; B=100-999 nM; C=1-99nM; and D=1-999 pM.

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A.

TABLE 2 Example Range 1 D 24-4e C 24-4f B 24-4g A 25-1 D 25-2 D 25-3 D25-4 D 25-5 D 25-6 C 25-7 C 25-8 D 24-4h D 120-9 D 120 D 120-5 C 120-6 C120-7 D 120-8 C 103-3 D 103-4 D 103-1 D 103-2 D 103-5 D 103-6 C 103-8 D103-7 D 151 isomer 1 C 151 isomer 2 B 152j-9 C 152j-10 C 152j-1 C 152j-2D 153c-5 C 153c-6 C 153c-2 C 153c-1 C 152j-7 C 152j-8 D 153c-3 A 153c-4A 152j-11 D 152j-12 D 152j-15 D 152j-28 D 152j-13 C 152j-14 C 152j-19 D152j-16 D 152j-3 D 152j-20 C 152j-17 D 152j-18 D 152j-3 D 152j-5 D152j-6 D 152l-2 D 152l-1 D 152j-24 D 152j-23 D 153c-7 C 152j-22 D24-18-2 D 24-18-1 D 24-18-4 D 24-18-5 D 24-18-6 D 24-18-3 D 152j-21 D152l-3 D 131.1-2 D 131.1-1 D 24-4a D 120-1 D 120-2 D 120-3 D 120-4 D24-10 D 24-9 D 24-8 D 24-11 C 24-12 C 11 C 24-16 D 24-18 D 24-17 D 24-15C 24-13 B 24-14 C 24-4b C 24-4c D 24-4d D 148 C 149 D 150 C 24-5 D 24-6D 24-7 D 24-1 D 24-2 D 24-3 D 28-1 D 28-2 D 28-3 D 28-4 D 28-5 D 84-1 D84-2 D 84-3 D 84-4 D 84-7 C 84-10 C 84-12 D 84-14 C 84-15 C 84-17 D84-18 C 84-19 C 84-20 C 84-24 D 84-26 D 84-27 D 84-28 D 84-32 D 84-33 D84-34 C 84-35 D 84-36 D 84-38 D 84-39 D 84-40 D 84-44 D 84-46 D 84-47 D84-48 D 84-49 D 84-50 D 84-51 D 84-52 D 84-53 D 84-54 D 84-55 D 84-56 D84-57 D 84-58 D 84-59 D 84-60 D 84-61 D 84-62 D 84-63 D 84-64 D 84-65C-D 84-66 C-D 84-67 D 84-68 C 84-69 D 84-70 C 84-71 C 84-72 C 84-73 C84-74 D 84-75 C 84-76 D 84-77 D 84-78 D 84-79 D 84-80 D 84-81 D 84-82 D84-83 D 84-84 D 84-85 D 84-86 D 84-87 D 94-1 D 94-2 C 94-3 D 94-6 C-D94-9 D 94-10 D 94-12 C 94-13 D 94-17 D 94-19 D 94-20 C 94-24 D 94-25 D94-26 D 94-27 C 94-30 D 94-32 C 94-33 C 94-34 C 94-36 D 94-37 C 94-38 D94-42 D 94-44 D 94-45 D 94-46 D 94-47 D 94-48 D 94-49 D 94-50 D 94-51 D94-52 D 94-53 D 94-54 D 94-55 D 94-56 D 107-1 D 107-2 D 107-3 D 107-4 D107-5 D 107-6 D 107-7 D 107-8 D 107-9 D 107-10 D 107-11 D 107-12 D107-13 D 107-14 D 107-15 D 107-16 D 107-17 D 107-18 D 107-19 D 107-20 D107-21 D 107-22 D 107-23 D 107-24 D 107-25 D 107-26 D 107-27 D 107-28 D107-29 D 107-30 D 107-31 D 107-32 D 107-33 D 107-34 D 107-35 D 107-36 D107-37 D 107-38 D 107-39 D 107-40 D 107-41 D 107-42 D 107-43 D 107-44 D2 D 3 D 4 D 5 C 6 C 7 D 8 D 24-23 D 9 C 10 C 11 C 12 C 13 C 14 B 15 C 16C 17 D 18 D 19 D 20 C 21 D 22 D 23 D 24 C 25 D 26 C 27 C 28 C 29 D 30 C31 D 32 C 33 D 34 D 35 D 36 D 37 D 38 D 39 D 40 D 41 D 42 D 43 D 44 D 45D 46 D 47 D 48 D 49 D 50 B 51 D 52 D 53 D 54 D 55 D 56 D 57 D 58 D 59 D60 D 61 D 62 D 63 D 64 D 65 C 67 D 68 D 69 D 70 C 71 D 72 C 73 D 74 D 75D 76 D 77 D 78 D 79 D 80 D 81 D 82 D 83 D 84 D 85 D 86 D 87 D 88 D 89 D90 D 91 D 92 D 93 D 94 D 95 D 96 D 97 D 98 D 99 D 100 D 101 D 102 D 103D 104 D 105 D 106 D 107 D 108 D 109 C 110 D 111 D 112 D 113 D 114 D 115D 116 D 117 D 118 D 119 D 120 D 121 D 122 D 123 D 124 D 125 D 126 D 127D 128 D 129 D 130 D 131 D 132 D 133 C 134 D 135 D 136 D 138 D 139 D 140D 141 D 142 C 143 D 144 D 145 D 146 D 147 D LS2 C LS3 C LS4 C LS16 C LS6B LS11 A LS14 D LS20 D LS21 D LS22 D LS23 D LS24 D LS25 D LS26 D LS27D′mer 1 D LS27 D′mer 2 D LS36 D LS37 D F5 D F6 D F7 D F8 D F14 D F15 DF16 D F17 D F20 B F21 B F22 B F25 D F26 C F27 C F28 C F29 C F30 C F32 BF33 B F34 C F35 B F37 B F38 D F39 D Diastereomer F41 D F43 D F48 D F49 CF51 D F52 D F53 D F54 D F55 D F56 D F57 D F58 D F60 D F61 C F62 C F63 DF64 C F65 B F66 C F67 C F69 B F70 B F71 D cj-48 B cj-49 C cj-50 D cj-51D cj-52 D cj-53 D cj-54 D cj-55 D cj-56 D cj-57 D cj-58 D cj-59 D cj-60D cj-61 D cj-62 D cj-63 D cj-64 D cj-65 D cj-66 D cj-67 D cj-68 D cj-69D cj-70 D cj-71 D cj-72 D cj-73 D cj-74 C cj-75 D cj-76 D cj-77 D cj-78D cj-79 D cj-80 D cj-81 D cj-82 D cj-83 D cj-84 D cj-85 D cj-86 D cj-87D cj-88 D cj-89 D cj-90 D cj-91 D cj-92 C cj-93 D cj-94 D cj-95 D cj-96D cj-97 D cj-98 D cj-99 D cj-100 D cj-101 D cj-102 D cj-103 D cj-104 Dcj-105 D cj-106 D cj-107 D cj-108 D cj-109 D cj-110 D cj-111 D cj-112 Dcj-113 D cj-114 D cj-115 D cj-116 D cj-117 D cj-118 D cj-119 D cj-120 Dcj-121 D cj-122 D cj-45 D cj-41 D cj-47 C cj-43 D cj-44 D cj-40 D cj-46D cj-42 D cj-36 D cj-37 D cj-38 D cj-39 D cj-32 D cj-33 D cj-34 D cj-35C cj-136 D cj-137 C cj-138 A cj-139 C cj-140 B cj-141 A cj-142 A cj-143A cj-144 D cj-145 C cj-146 B cj-147 C cj-148 C cj-149 C cj-150 C cj-151C cj-152 C cj-153 D cj-154 D cj-155 C cj-156 D cj-126 D cj-127 C cj-128D cj-129 D cj-130 D cj-131 C cj-132 B cj-133 C cj-134 C cj-135 C cj-125C cj-15c D cj-20c D cj-20b D cj-20a D cj-17 D cj-16 D cj-20d D cj-20 Dcj-15a D cj-15 D cj-15d D cj-11n C cj-11o C cj-11p D cj-11m C cj-11h Dcj-11i D cj-11j D cj-11k D cj-11e A cj-11f C cj-11g C cj-11d D cj-11b Dcj-11 D cj-11a D cj-11c D JG-3 D JG-4 C JG-5 D JG-6 C JG-7 D JG-8 D JG-9D JG-10 C JG-12 D JG-13 C JG-14 D JG-15 D JG-16 D JG-17 D OL-1 D OL-2 DOL-3 C OL-4 D OL-5 D OL-6 D OL-7 D OL-8 D OL-9 D OL-10 D OL-11 D OL-12 DOL-13 D OL-19 D OL-20 C OL-21 D D73 D D74 D D75 D D76 D D77 D J16 D J17D J18 D J19 D J20 D J21 D J22 D J23 D J24 D J25 D J26 D J27 D J28 C J29D J30 C J31 D J37 D J38 D J39 D J40 D J41 D J42 D J42.a D J45 D J46 DJ47 D J48 D J49 D J50 D J51 C D33 D D34 D D35 D D36 D D37 D D38 D D39 DD40 D D41 D D42 D D43 D D44 D D45 D D46 D D47 D D48 D D49 D D50 D D51 DD52 D D53 D D54 D D55 D D56 D D57 D D58 D D59 D D60 D D61 D D62 D D63 DD64 D D65 D D66 D D67 D D68 D D69 D D70 D M1 >A M2 C M3 C M4 B M5 A M6 AM7 >A M8 A M9 B M10 >A M11 C M12 C M13 B M14 B M15 B M16 A M17 B M18 AM19 >A M21 C M22 A M23 C M24 C M25 C M26 B M27 C M28 A M28-2 B M29 >AM30 C M31 C M32 B M33 C M34 C M35 C M36 C M37 C M38 C M39 C M40 C M41 CM42 C M43 C M44 B M45 C M46 C M47 C M48 C M49 C M50 C M51 C M52 C M53 CM54 C M55 C M56 C M57 C M58 C M59 C M60 C M61 C M62 C M63 C M64 C M65 CM66a B M66b B M66x C M67a B M67b B M68 B M69 B M70 C M71 C M72 C M73 BM74 C M75 C M76 C M77 C M78 C M79 C M80 C M81 B M82 C M83 C M84 C M85 CM86 C M87 C M88 C M89 C M90 A M91 C M91x C M91y B M92 A M93 C M94 C M95C M96 B M97 C M98 C M99 C M100 C M101 B M102 C M103 B M104 B M105 C M106C M107 C M108 C M109 C M110 C M111 A M112 C M113 C M114 >A M115 >AM116 >A M117 >A M118 >A M119 B M120 B M121 B M122 C M123 A M124 C M125 CM126 C M127 C M128 C M129 A M130 C M131 D M132 D M133 D M134 C M135 DM136 C M137 D M138 D M139 D M140 D M140a-ii C M140a-i C M141 C M142 CM143 C M144 D M145 D M146 D M147 D M148 D M149 C M150 D M151 D M152 M153D M154 D M155 C M156 C M157 D M158 C M159 D M160 C M161 C M162 C E5 DE5a D E5b D E5c D E5d D E5e D E5f D E5g D E5h D E5i D E5j D E5k D E51 DE5m D J14 D J14a D J14a.1 D J14b D J14b.1 D J14c D J14c.1 D J14c.2 DJ14e D J14e.1 D J14f D J14f.1 C

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A.Compounds of the present disclosure may inhibit multiple genotypes ofHCV.

1. A compound selected from methyl((1S)-2-((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-L-alanyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-1-methyl-2-oxoethyl)carbamate;dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate;methyl(2-((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-(((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate;dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate;dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate;methyl((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-acetyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;methyl((1S)-2-methyl-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl-2-methylpropyl)carbamate;tert-butyl((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;N-((1S)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2S)-2-((cyclopropylcarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)cyclopropanecarbamate;tert-butyl((1R)-1-(((1R,3S,5R)-3-(4-(4′-(2-((1R,3S,5R)-2-((2R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;andN,N′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))di(2-pyrimidinamine);or a pharmaceutically acceptable salt thereof.
 2. A compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 3. The compositionof claim 2 further comprising one or two additional compounds havinganti-HCV activity.
 4. The composition of claim 3 wherein at least one ofthe additional compounds is an interferon or a ribavirin.
 5. Thecomposition of claim 4 wherein the interferon is selected frominterferon alpha 2B, pegylated interferon alpha, consensus interferon,interferon alpha 2A, and lymphoblastiod interferon tau.
 6. Thecomposition of claim 3 wherein at least one of the additional compoundsis selected from interleukin 2, interleukin 6, interleukin 12, acompound that enhances the development of a type 1 helper T cellresponse, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, aninosine 5′-monophospate dehydrogenase inhibitor, amantadine, andrimantadine.
 7. The composition of claim 3 wherein at least one of theadditional compounds is effective to inhibit the function of a targetselected from HCV metalloprotease, HCV serine protease, HCV polymerase,HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCVNS5A protein, and IMPDH for the treatment of an HCV infection.
 8. Amethod of relieving or causing regression of an HCV infection in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 9. The method of claim 8 further comprisingadministering one or two additional compounds having anti-HCV activityprior to, after or simultaneously with the compound of claim 2, or apharmaceutically acceptable salt thereof.
 10. The method of claim 9wherein at least one of the additional compounds is an interferon or aribavirin.
 11. The method of claim 10 wherein the interferon is selectedfrom interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastiod interferon tau. 12.The method of claim 9 wherein at least one of the additional compoundsis selected from interleukin 2, interleukin 6, interleukin 12, acompound that enhances the development of a type 1 helper T cellresponse, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, aninosine 5′-monophospate dehydrogenase inhibitor, amantadine, andrimantadine.
 13. The method of claim 9 wherein at least one of theadditional compounds is effective to inhibit the function of a targetselected from HCV metalloprotease, HCV serine protease, HCV polymerase,HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCVNS5A protein, and IMPDH for the treatment of an HCV infection.